Cyclohexylimidiazole lactam derivatives as inhibitors of 11-beta-hydroxysteroid dehydrogenase 1

ABSTRACT

The present invention discloses novel compounds of Formula I: (I) having 11β-HSD type 1 antagonist activity, as well as methods for preparing such compounds. In another embodiment, the invention discloses pharmaceutical compositions comprising compounds of Formula I, as well as methods of using the compounds and compositions to treat diabetes, hyperglycemia, obesity, hypertension, hyperlipidemia, metabolic syndrome, and other conditions associated with 11β-HSD type 1 activity.

This application claims the benefit of U.S. Provisional Application No.60/745,321 filed Apr. 21, 2006.

This invention relates to compounds that are inhibitors of11-β-hydroxysteroid dehydrogenase type 1 (“11-β-HSD1”), and topharmaceutical compositions thereof, and the uses of these compounds andcompositions in the treatment of the human or animal body, and to novelintermediates useful in preparation of the inhibitors. The presentcompounds show potent and selective inhibition of 11-β-HSD1, and as suchare useful in the treatment of disorders responsive to the modulation of11-β-HSD1, such as diabetes, metabolic syndrome, cognitive disorders,and the like.

Glucocorticoids acting in the liver, adipose tissue, and muscle, areimportant regulators of glucose, lipid, and protein metabolism. Chronicglucocorticoid excess is associated with insulin resistance, visceralobesity, hypertension, and dyslipidemia, which also represent theclassical hallmarks of metabolic syndrome. 11-β-HSD1 catalyses theconversion of inactive cortisone to active cortisol, and has beenimplicated in the development of metabolic syndrome. Evidence in rodentsand humans links 11-β-HSD1 to metabolic syndrome. Evidence suggests thata drug which specifically inhibits 11-β-HSD1 in type 2 diabetic patientswill lower blood glucose by reducing hepatic gluconeogenesis, reducecentral obesity, improve atherogenic lipoprotein phenotypes, lower bloodpressure, and reduce insulin resistance. Insulin effects in muscle willbe enhanced, and insulin secretion from the beta cells of the islet mayalso be increased. Evidence from animal and human studies also indicatesthat an excess of glucocorticoids impair cognitive function. Recentresults indicate that inactivation of 11-β-HSD1 enhances memory functionin both men and mice. The 11-β-HSD inhibitor carbenoxolone was shown toimprove cognitive function in healthy elderly men and type 2 diabetics,and inactivation of the 11-β-HSD1 gene prevented aging-inducedimpairment in mice. Selective inhibition of 11-β-HSD1 with apharmaceutical agent has recently been shown to improve memory retentionin mice.

A number of publications have appeared in recent years reporting agentsthat inhibit 11-β-HSD1. See International Application WO2004/056744which discloses adamantyl acetamides as inhibitors of 11-β-HSD,International Application WO2005/108360 which discloses pyrrolidin-2-oneand piperidin-2-one derivatives as inhibitors of 11-β-HSD, andInternational Application WO2005/108361 which discloses adamantylpyrrolidin-2-one derivatives as inhibitors of 11-β-HSD. In spite of thenumber of treatments for diseases that involve 11-β-HSD1, the currenttherapies suffer from one or more inadequacies, including poor orincomplete efficacy, unacceptable side effects, and contraindicationsfor certain patient populations. Thus, there remains a need for animproved treatment using alternative or improved pharmaceutical agentsthat inhibit 11-β-HSD1 and treat the diseases that could benefit from11-β-HSD1 inhibition. The present invention provides such a contributionto the art based on the finding that a novel class of compounds has apotent and selective inhibitory activity on 11-β-HSD1. The presentinvention is distinct in the particular structures and their activities.There is a continuing need for new methods of treating diabetes,metabolic syndrome, and cognitive disorders, and it is an object of thisinvention to meet these and other needs.

The present invention provides a compound structurally represented byformula I:

or a pharmaceutically acceptable salt thereof, whereinR¹ is —H, -halogen, —O—CH₃ (optionally substituted with one to threehalogens), or —CH₃ (optionally substituted with one to three halogens);R² is —H, -halogen, —O—CH₃ (optionally substituted with one to threehalogens), or —CH₃ (optionally substituted with one to three halogens);R³ is —H or -halogen;

R⁴ is

-   -   —OH, halogen, cyano, —(C₁-C₄)alkyl(optionally substituted with        one to three halogens), —(C₁-C₆)alkoxy(optionally substituted        with one to three halogens), —SCF₃, —C(O)O(C₁-C₄)alkyl,        —(C₃-C₈)cycloalkyl, —O-phenyl-C(O)O—(C₁-C₄)alkyl, —CH₂-phenyl,        —NHSO₂—(C₁-C₄)alkyl,    -   —NHSO₂-phenyl(R²¹)(R²¹), —(C₁-C₄)alkyl-C(O)N(R¹⁰)(R¹¹),

wherein the dashed line represents the point of attachment to the R⁴position in formula I;

R¹ is

-   -   —H, -halogen, —(C₁-C₄)alkyl(optionally substituted with 1 to 3        halogens), —C(O)OH, —C(O)O—(C₁-C₄)alkyl, —C(O)—(C₁-C₄)alkyl,        —O—(C₁-C₄)alkyl(optionally substituted with 1 to 3 halogens),        —SO₂—(C₁-C₄)alkyl, —N(R⁸)(R⁸),

wherein the dashed line represents the point of attachment to theposition indicated by R⁵;

wherein m is 1, 2, or 3;

wherein n is 0, 1, or 2, and wherein when n is 0, then “(CH₂)n” is abond;

R⁶ is

—H, -halogen, —CN, or —(C₁-C₄)alkyl(optionally substituted with 1 to 3halogens);

R⁷ is

—H, -halogen, or —(C₁-C₄)alkyl(optionally substituted with 1 to 3halogens);

R⁸ is independently at each occurrence

—H, —(C₁-C₆)alkyl(optionally substituted with 1 to 3 halogens),

—C(O)—(C₁-C₆)alkyl(optionally substituted with 1 to 3 halogens),

—C(O)—(C₃-C₈)cycloalkyl, —S(O₂)—(C₃-C₈)cycloalkyl or

—S(O₂)—(C₁-C₃)alkyl(optionally substituted with 1 to 3 halogens);

R⁹ is —H or -halogen;R¹⁰ and R¹¹ are each independently

-   -   —H or —(C₁-C₄)alkyl, or R¹⁰ and R¹¹ taken together with the        nitrogen to which they are attached form piperidinyl,        piperazinyl, or pyrrolidinyl;        R²⁰ is independently at each occurrence —H, or        —(C₁-C₃)alkyl(optionally substituted with 1 to 3 halogens);        R²¹ is independently at each occurrence —H, -halogen, or        —(C₁-C₃)alkyl(optionally substituted with 1 to 3 halogens);        R²² is independently at each occurrence —H or        —(C₁-C₆)alkyl(optionally substituted with 1 to 3 halogens); and        R²³ is independently at each occurrence —H, —(C₁-C₄)alkyl, or        —C(O)O—(C₁-C₄)alkyl.

The present invention provides compounds of formula I that are useful aspotent and selective inhibition of 11-β-HSD1. The present inventionfurther provides a pharmaceutical composition which comprises a compoundof Formula I, or a pharmaceutical salt thereof, and a pharmaceuticallyacceptable carrier, diluent, or excipient. In addition, the presentinvention provides a method for the treatment of metabolic syndrome, andrelated disorders, which comprise administering to a patient in needthereof an effective amount of a compound of formula I or apharmaceutically acceptable salt thereof.

In one embodiment, the present invention provides compounds of Formula Ior a pharmaceutically acceptable salt thereof as described in detailabove. While all of the compounds of the present invention are useful,certain of the compounds are particularly interesting and are preferred.The following listings set out several groups of preferred compounds.

In another embodiment the invention provides a compound structurallyrepresented by formula Ia;

or a pharmaceutically acceptable salt thereof, wherein

R^(o) is

wherein the dashed line represents the point of attachment to the R⁰position in formula Ia;R¹ is -halogen; R² is -halogen; R³ is —H or -halogen;

R⁴ is

wherein the dashed line represents the point of attachment to the R⁴position in formula Ia;

R⁵ is

-   -   —H, -halogen, —(C₁-C₄)alkyl(optionally substituted with 1 to 3        halogens), —C(O)OH, —C(O)O—(C₁-C₄)alkyl, —C(O)—(C₁-C₄)alkyl,        —O—(C₁-C₄)alkyl(optionally substituted with 1 to 3 halogens),        —SO₂—(C₁-C₄)alkyl, —N(R⁸)(R⁸),

wherein the dashed line represents the point of attachment to theposition indicated by R⁵;

wherein m is 1, 2, or 3;

wherein n is 0, 1, or 2, and wherein when n is 0, then “(CH₂)n” is abond;

R⁶ is

—H, -halogen, —CN, or —(C₁-C₄)alkyl(optionally substituted with 1 to 3halogens);

R⁷ is

—H, -halogen, or —(C₁-C₄)alkyl(optionally substituted with 1 to 3halogens);

R⁸ is independently at each occurrence

—H, —(C₁-C₆)alkyl(optionally substituted with 1 to 3 halogens),

—C(O)—(C₁-C₆)alkyl(optionally substituted with 1 to 3 halogens),

—C(O)—(C₃-C₈)cycloalkyl, —S(O₂)—(C₃-C₈)cycloalkyl or

—S(O₂)—(C₁-C₃)alkyl(optionally substituted with 1 to 3 halogens);

R⁹ is —H or -halogen;R²⁰ is independently at each occurrence —H, or —(C₁-C₃)alkyl(optionallysubstituted with 1 to 3 halogens);R²¹ is independently at each occurrence —H, -halogen, or—(C₁-C₃)alkyl(optionally substituted with 1 to 3 halogens);R²² is independently at each occurrence —H or —(C₁-C₆)alkyl(optionallysubstituted with 1 to 3 halogens); andR²³ is independently at each occurrence —H, —(C₁-C₄)alkyl, or—C(O)O—(C₁-C₄)alkyl.

In another embodiment the invention provides a compound structurallyrepresented by formula Ia;

or a pharmaceutically acceptable salt thereof, wherein

R⁰ is

wherein the dashed line represents the point of attachment to the R⁰position in formula Ia;R¹ is -chlorine, -fluorine, or -bromine; R² is -chlorine, -fluorine, or-bromine; R³ is —H or -halogen;

R⁴ is

wherein the dashed line represents the point of attachment to the R⁴position in formula Ia;

R⁵ is

-   -   —H, -halogen, —(C₁-C₄)alkyl(optionally substituted with 1 to 3        halogens), —C(O)OH, —C(O)O—(C₁-C₄)alkyl, —C(O)—(C₁-C₄)alkyl,        —O—(C₁-C₄)alkyl(optionally substituted with 1 to 3 halogens),        —SO₂—(C₁-C₄)alkyl, —N(R⁸)(R⁸),

wherein the dashed line represents the point of attachment to theposition indicated by R⁵; wherein m is 1, 2, or 3;

R⁶ is

—H, -halogen, —CN, or —(C₁-C₄)alkyl(optionally substituted with 1 to 3halogens);

R⁷ is

—H, -halogen, or —(C₁-C₄)alkyl(optionally substituted with 1 to 3halogens);

R⁸ is independently at each occurrence

—H, —(C₁-C₆)alkyl(optionally substituted with 1 to 3 halogens),

—C(O)—(C₁-C₆)alkyl(optionally substituted with 1 to 3 halogens),

—C(O)—(C₃-C₈)cycloalkyl, —S(O₂)—(C₃-C₈)cycloalkyl or

—S(O₂)—(C₁-C₃)alkyl(optionally substituted with 1 to 3 halogens);

R⁹ is —H or -halogen;R²⁰ is independently at each occurrence —H, or —(C₁-C₃)alkyl(optionallysubstituted with 1 to 3 halogens);R²¹ is independently at each occurrence —H, -halogen, or—(C₁-C₃)alkyl(optionally substituted with 1 to 3 halogens);R²² is independently at each occurrence —H or —(C₁-C₆)alkyl(optionallysubstituted with 1 to 3 halogens); andR²³ is independently at each occurrence —H, —(C₁-C₄)alkyl, or—C(O)O—(C₁-C₄)alkyl.

In another embodiment the invention provides a compound structurallyrepresented by formula Ia;

or a pharmaceutically acceptable salt thereof, wherein

R⁰ is

wherein the dashed line represents the point of attachment to the R⁰position in formula Ia;R¹ is -chlorine, -fluorine, or -bromine; R² is -chlorine, -fluorine, or-bromine; R³ is —H or -halogen;

R⁴ is

wherein the dashed line represents the point of attachment to the R⁴position in formula Ia;

R⁵ is

-   -   —H, -halogen, —(C₁-C₄)alkyl(optionally substituted with 1 to 3        halogens), —C(O)OH, —C(O)O—(C₁-C₄)alkyl, —C(O)—(C₁-C₄)alkyl,        —O—(C₁-C₄)alkyl(optionally substituted with 1 to 3 halogens),        —SO₂—(C₁-C₄)alkyl, —N(R⁸)(R⁸),

wherein the dashed line represents the point of attachment to theposition indicated by R⁵; wherein m is 1, 2, or 3;

R⁶ is

—H, -halogen, —CN, or —(C₁-C₄)alkyl(optionally substituted with 1 to 3halogens);

R⁷ is

—H, -halogen, or —(C₁-C₄)alkyl(optionally substituted with 1 to 3halogens);

R⁸ is independently at each occurrence

—H, —(C₁-C₆)alkyl(optionally substituted with 1 to 3 halogens),

—C(O)—(C₁-C₆)alkyl(optionally substituted with 1 to 3 halogens),

—C(O)—(C₃-C₈)cycloalkyl, —S(O₂)—(C₃-C₈)cycloalkyl or

—S(O₂)—(C₁-C₃)alkyl(optionally substituted with 1 to 3 halogens);

R⁹ is —H or -halogen;R²⁰ is independently at each occurrence —H, or —(C₁-C₃)alkyl(optionallysubstituted with 1 to 3 halogens);R²¹ is independently at each occurrence —H, -halogen, or—(C₁-C₃)alkyl(optionally substituted with 1 to 3 halogens);R²² is independently at each occurrence —H or —(C₁-C₆)alkyl(optionallysubstituted with 1 to 3 halogens); andR²³ is independently at each occurrence —H, —(C₁-C₄)alkyl, or—C(O)O—(C₁-C₄)alkyl.

In another embodiment the invention provides a compound structurallyrepresented by formula Ia;

or a pharmaceutically acceptable salt thereof, wherein

R⁰ is

wherein the dashed line represents the point of attachment to the R⁰position in formula Ia;R¹ is -chlorine, -fluorine, or -bromine; R² is -chlorine, -fluorine, or-bromine; R³ is —H or -halogen;

R⁴ is

wherein the dashed line represents the point of attachment to the R⁴position in formula Ia;

R⁵ is

wherein the dashed line represents the point of attachment to theposition indicated by R⁵;

R⁶ is

—H, -halogen, —CN, or —(C₁-C₄)alkyl(optionally substituted with 1 to 3halogens);

R⁷ is

—H, -halogen, or —(C₁-C₄)alkyl(optionally substituted with 1 to 3halogens);

R⁸ is independently at each occurrence

—H, —(C₁-C₆)alkyl(optionally substituted with 1 to 3 halogens),

—C(O)—(C₁-C₆)alkyl(optionally substituted with 1 to 3 halogens),

—C(O)—(C₃-C₈)cycloalkyl, —S(O₂)—(C₃-C₈)cycloalkyl or

—S(O₂)—(C₁-C₃)alkyl(optionally substituted with 1 to 3 halogens);

R⁹ is —H or -halogen;R²⁰ is independently at each occurrence —H, or —(C₁-C₃)alkyl(optionallysubstituted with 1 to 3 halogens);R²¹ is independently at each occurrence —H, -halogen, or—(C₁-C₃)alkyl(optionally substituted with 1 to 3 halogens);R²² is independently at each occurrence —H or —(C₁-C₆)alkyl(optionallysubstituted with 1 to 3 halogens); andR²³ is independently at each occurrence —H, —(C₁-C₄)alkyl, or—C(O)O—(C₁-C₄)alkyl.

In another embodiment the invention provides a compound structurallyrepresented by formula Ia;

or a pharmaceutically acceptable salt thereof, wherein

R⁰ is

wherein the dashed line represents the point of attachment to the R⁰position in formula Ia;R¹ is -chlorine, -fluorine, or -bromine; R² is -chlorine, -fluorine, or-bromine; R³ is —H or -halogen;

R⁴ is

wherein the dashed line represents the point of attachment to the R⁴position in formula Ia;

R⁵ is

—SO₂—(C₁-C₄)alkyl,

wherein the dashed line represents the point of attachment to theposition indicated by R⁵; wherein m is 1, 2, or 3;

R⁶ is

—H, -halogen, —CN, or —(C₁-C₄)alkyl(optionally substituted with 1 to 3halogens);

R⁷ is

—H, -halogen, or —(C₁-C₄)alkyl(optionally substituted with 1 to 3halogens); and

R⁸ is independently at each occurrence

—H, —(C₁-C₆)alkyl(optionally substituted with 1 to 3 halogens),

—C(O)—(C₁-C₆)alkyl(optionally substituted with 1 to 3 halogens),

—C(O)—(C₃-C₈)cycloalkyl, —S(O₂)—(C₃-C₈)cycloalkyl or

—S(O₂)—(C₁-C₃)alkyl(optionally substituted with 1 to 3 halogens).

In another embodiment the invention provides a compound structurallyrepresented by formula Ia;

or a pharmaceutically acceptable salt thereof, wherein

R⁰ is

wherein the dashed line represents the point of attachment to the R⁰position in formula Ia;R¹ is -chlorine, -fluorine, or -bromine; R² is -chlorine, -fluorine, or-bromine; R³ is —H or -halogen;

R⁴ is

wherein the dashed line represents the point of attachment to the R⁴position in formula Ia;

R⁵ is

—N(R⁸)(R⁸),

-   -   wherein the dashed line represents the point of attachment to        the position indicated by R⁵;

R⁶ is

—H, -halogen, —CN, or —(C₁-C₄)alkyl(optionally substituted with 1 to 3halogens);

R⁷ is

—H, -halogen, or —(C₁-C₄)alkyl(optionally substituted with 1 to 3halogens); and

R⁸ is independently at each occurrence

—H, —(C₁-C₆)alkyl(optionally substituted with 1 to 3 halogens),

—C(O)—(C₁-C₆)alkyl(optionally substituted with 1 to 3 halogens),

—C(O)—(C₃-C₈)cycloalkyl, —S(O₂)—(C₃-C₈)cycloalkyl or

—S(O₂)—(C₁-C₃)alkyl(optionally substituted with 1 to 3 halogens).

Other embodiments of the invention are provided wherein each of theembodiments described herein above is further narrowed as described inthe following preferences. Specifically, each of the preferences belowis independently combined with each of the embodiments above, and theparticular combination provides another embodiment in which the variableindicated in the preference is narrowed according to the preference.

Preferably embodiments of the invention are structurally represented bythe formula:

wherein R⁰ is

or a stereoisomer thereof, or a pharmaceutically acceptable saltthereof.

Preferably R⁰ is

Preferably R⁰ is

Preferably R¹ is -halogen. Preferably R¹ is —CH₃. Preferably R¹ is-chlorine, -fluorine, or -bromine. Preferably R¹ is -chlorine.Preferably R¹ is -fluorine. Preferably R¹ is -bromine. Preferably R² is-halogen. Preferably R² is —CH₃ Preferably R² is -chlorine, -fluorine,or -bromine. Preferably R² is -chlorine. Preferably R² is -fluorine.Preferably R² is -bromine. Preferably R¹ is -chlorine and R² is-chlorine. Preferably R³ is —H. Preferably R³ is -halogen.

Preferably R⁴ is

Preferably R⁴ is

Preferably R⁴ is

Preferably R⁴ is

and R⁶ is hydrogen. Preferably R⁴ is

Preferably R⁴ is

and R⁷

is hydrogen. Preferably R⁴ is

Preferably R⁴ is

Preferably R⁴ is

Preferably R⁴ is

Preferably R⁴ is

Preferably R⁵ is —N(R⁸)(R⁸),

Preferably R⁵ is —SO₂—(C₁-C₄)alkyl,

Preferably R⁵ is

Preferably R⁵ is

and R⁸ is —(C₁-C₃)alkyl(optionally substituted with 1 to 3 halogens).Preferably R⁵ is halogen. Preferably R⁵ is chlorine. Preferably R⁵ isfluorine.Preferably R⁶ is —H. Preferably R⁶ is -halogen. Preferably R⁶ is—(C₁-C₄)alkyl(optionally substituted with 1 to 3 halogens). PreferablyR⁷ is —H. Preferably R⁷ is -halogen, or —(C₁-C₄)alkyl(optionallysubstituted with 1 to 3 halogens). Preferably R⁷ is -halogen. PreferablyR⁷ is —(C₁-C₄)alkyl(optionally substituted with 1 to 3 halogens).Preferably R⁸ is independently at each occurrence —H. Preferably R⁸ isindependently at each occurrence —(C₁-C₃)alkyl. Preferably R⁸ isindependently at each occurrence —CH₃. Preferably R⁹ is —H. PreferablyR⁹ is -halogen. Preferably R⁷ is -fluorine and R⁹ is -fluorine.

In another embodiment the invention provides a compound structurallyrepresented by formula Ia, or a pharmaceutically acceptable saltthereof, wherein

R⁰ is

wherein the dashed line represents the point of attachment to the R⁰position in formula Ia; R¹ is -chlorine; R² is -chlorine; R³ is —H;

wherein the dashed line represents the point of attachment to the R⁴position in formula Ia;

R⁵ is

-   -   —H, -chlorine, -fluorine, —CH₃, —CF₃, —C(CH₃)₃, —CH(CH₃)₂,        —O—C(CH₃)₂—C(O)O—CH₃, —N(—CH₃)(—CH₃),

wherein the dashed line represents the point of attachment to theposition indicated by R⁵; wherein m is 1, 2, or 3;R⁶ is —H, -chlorine, -fluorine, -bromine, —CH₃, CF₃;R⁷ is —H, -chlorine, -fluorine, -bromine ;R⁸ is independently at each occurrence —H or —CH₃, —CH₂—CH₃, —C(CH₃)₃,—CH(CH₃)₂;R⁹ is —H or -chlorine, -fluorine, -bromine;R²⁰ is independently at each occurrence —H, —CH₃; andR²² is independently at each occurrence —H.

Preferred embodiments of the invention are compounds of the formula(R)-3-(3,5-Dichloro-4′-morpholin-4-yl-biphenyl-4-ylmethyl)-1-(4,5,6,7-tetrahydro-1H-benzoimidazol-5-yl)-pyrrolidin-2-one,(R)-3-[2,6-Dichloro-4-(2-fluoro-6-morpholin-4-yl-pyridin-3-yl)-benzyl]-1-(4,5,6,7-tetrahydro-1H-benzoimidazol-5-yl)-pyrrolidin-2-one,and3-[R]-[3,5-Dichloro-4′-(4-trifluoromethyl-piperidine-1-carbonyl)-biphenyl-4-ylmethyl]-1-(4,5,6,7-tetrahydro-3H-benzoimidazol-5-yl)-pyrrolidin-2-one,or3-(3,5-Dichloro-4′-fluoro-biphenyl-4-ylmethyl)-1-(4,5,6,7-tetrahydro-1H-benzoimidazol-5-yl)-pyrrolidin-2-one;or stereoisomers thereof, or a pharmaceutically acceptable saltsthereof. A further embodiment of the invention are the novelintermediate preparations described herein which are useful forpreparing the 11-β-HSD1 inhibitors according to formula I and theembodiments described herein.

Patients with type 2 diabetes often develop “insulin resistance” whichresults in abnormal glucose homeostasis and hyperglycemia leading toincreased morbidity and premature mortality. Abnormal glucosehomeostasis is associated with obesity, hypertension, and alterations inlipid, lipoprotein, and apolipoprotein metabolism. Type 2 diabetics areat increased risk of developing cardiovascular complications, e.g.,atherosclerosis, coronary heart disease, stroke, peripheral vasculardisease, hypertension, nephropathy, neuropathy, and retinopathy.Therefore, therapeutic control of glucose homeostasis, lipid metabolism,obesity, and hypertension are important in the management and treatmentof diabetes mellitus. Many patients who have insulin resistance but havenot developed type 2 diabetes are also at risk of developing “SyndromeX” or “Metabolic syndrome”. Metabolic syndrome is characterized byinsulin resistance along with abdominal obesity, hyperinsulinemia, highblood pressure, low HDL, high VLDL, hypertension, atherosclerosis,coronary heart disease, and chronic renal failure. These patients are atincreased risk of developing the cardiovascular complications listedabove whether or not they develop overt diabetes mellitus.

Due to their inhibition of 11-β-HSD1, the present compounds are usefulin the treatment of a wide range of conditions and disorders in whichinhibition of 11-β-HSD1 is beneficial. These disorders and conditionsare defined herein as “diabetic disorders” and “metabolic syndromedisorders”. One of skill in the art is able to identify “diabeticdisorders” and “metabolic syndrome disorders” by the involvement of11-β-HSD1 activity either in the pathophysiology of the disorder, or inthe homeostatic response to the disorder. Thus, the compounds may finduse for example to prevent, treat, or alleviate, diseases or conditionsor associated symptoms or sequelae, of “Diabetic disorders” and“metabolic syndrome disorders”.

“Diabetic disorders” and “metabolic syndrome disorders” include, but arenot limited to, diabetes, type 1 diabetes, type 2 diabetes,hyperglycemia, hyper insulinemia, beta-cell rest, improved beta-cellfunction by restoring first phase response, prandial hyperglycemia,preventing apoptosis, impaired fasting glucose (IFG), metabolicsyndrome, hypoglycemia, hyper-/hypokalemia, normalizing glucagon levels,improved LDL/HDL ratio, reducing snacking, eating disorders, weightloss, polycystic ovarian syndrome (PCOS), obesity as a consequence ofdiabetes, latent autoimmune diabetes in adults (LADA), insulitis, islettransplantation, pediatric diabetes, gestational diabetes, diabetic latecomplications, micro-/macroalbuminuria, nephropathy, retinopathy,neuropathy, diabetic foot ulcers, reduced intestinal motility due toglucagon administration, short bowel syndrome, antidiarrheic, increasinggastric secretion, decreased blood flow, erectile dysfunction, glaucoma,post surgical stress, ameliorating organ tissue injury caused byreperfusion of blood flow after ischemia, ischemic heart damage, heartinsufficiency, congestive heart failure, stroke, myocardial infarction,arrhythmia, premature death, anti-apoptosis, wound healing, impairedglucose tolerance (IGT), insulin resistance syndromes, metabolicsyndrome, syndrome X, hyperlipidemia, dyslipidemia,hypertriglyceridemia, hyperlipoproteinemia, hypercholesterolemia,arteriosclerosis including atherosclerosis, glucagonomas, acutepancreatitis, cardiovascular diseases, hypertension, cardiachypertrophy, gastrointestinal disorders, obesity, diabetes as aconsequence of obesity, diabetic dyslipidemia, etc. Thus the presentinvention also provides a method of treatment of “Diabetic disorders”and “metabolic syndrome disorders” while reducing and or eliminating oneor more of the unwanted side effects associated with the currenttreatments.

In addition, the present invention provides a compound of Formula I, ora pharmaceutical salt thereof, or a pharmaceutical composition whichcomprises a compound of Formula I, or a pharmaceutical salt thereof, anda pharmaceutically acceptable carrier, diluent, or excipient: for use ininhibiting 11-β-HSD1 activity; for use in inhibiting a 11-β-HSD1activity mediated cellular response in a mammal; for use in reducing theglycemic level in a mammal; for use in treating a disease arising fromexcessive 11-β-HSD1 activity; for use in treating diabetic and othermetabolic syndrome disorders in a mammal; and for use in treatingdiabetes, metabolic syndrome, obesity, hyperglycemia, atherosclerosis,ischemic heart disease, stroke, neuropathy, and wound healing. Thus, themethods of this invention encompass a prophylactic and therapeuticadministration of a compound of Formula I.

The present invention further provides the use of a compound of FormulaI, or a pharmaceutical salt thereof for the manufacture of a medicamentfor inhibiting 11-β-HSD1 activity; for the manufacture of a medicamentfor inhibiting 11-β-HSD1 activity mediated cellular response in amammal; for the manufacture of a medicament for reducing the glycemiclevel in a mammal; for the manufacture of a medicament for treating adisease arising from excessive 11-β-HSD1 activity; for the manufactureof a medicament for treating diabetic and other metabolic syndromedisorders in a mammal; and for the manufacture of a medicament forpreventing or treating diabetes, metabolic syndrome, obesity,hyperglycemia, atherosclerosis, ischemic heart disease, stroke,neuropathy, and improper wound healing.

The present invention further provides a method of treating conditionsresulting from excessive 11-β-HSD1 activity in a mammal; a method ofinhibiting 11-β-HSD1 activity in a mammal; a method of inhibiting a11-β-HSD1 activity mediated cellular response in a mammal; a method ofreducing the glycemic level in a mammal; a method of treating diabeticand other metabolic syndrome disorders in a mammal; a method ofpreventing or treating diabetes, metabolic syndrome, obesity,hyperglycemia, atherosclerosis, ischemic heart disease, stroke,neuropathy, and improper wound healing; said methods comprisingadministering to a mammal in need of such treatment a 11-β-HSD1 activityinhibiting amount of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition which comprisesa compound of Formula I, or a pharmaceutical salt thereof, and apharmaceutically acceptable carrier, diluent, or excipient.

In addition, the present invention provides a pharmaceutical compositionwhich comprises a compound of Formula I, or a pharmaceutical saltthereof, and a pharmaceutically acceptable carrier, diluent, orexcipient: adapted for use in inhibiting 11-β-HSD1 activity; adapted foruse in inhibiting 11-β-HSD1 activity mediated cellular responses;adapted for use in reducing the glycemic level in a mammal; adapted foruse in treating diabetic and other metabolic syndrome disorders in amammal; and adapted for use in preventing or treating diabetes,metabolic syndrome, obesity, hyperglycemia, atherosclerosis, ischemicheart disease, stroke, neuropathy, and wound healing.

In a further aspect of the invention the present compounds areadministered in combination with one or more further active substancesin any suitable ratios. Such further active substances may for examplebe selected from antidiabetics, antiobesity agents, antihypertensiveagents, agents for the treatment of complications resulting from orassociated with diabetes and agents for the treatment of complicationsand disorders resulting from or associated with obesity. The followinglisting sets out several groups of combinations. It will be understoodthat each of the agents named may be combined with other agents named tocreate additional combinations.

Thus, in a further embodiment of the invention the present compounds maybe administered in combination with one or more antidiabetics.

Suitable antidiabetic agents include insulin, insulin analogues andderivatives such as those disclosed in EP 792 290 (Novo Nordisk A/S),for example N^(εB29)-tetradecanoyl des (B30) human insulin, EP 214 826and EP 705 275 (Novo Nordisk A/S), for example ASP^(B28) human insulin,U.S. Pat. No. 5,504,188 (Eli Lilly), for example LySB²⁸ ProB²⁹ humaninsulin, EP 368 187 (Aventis), for example Lantus®, GLP-1 and GLP-1derivatives such as those disclosed in WO 98/08871 (Novo Nordisk A/S),as well as orally active hypoglycemic agents.

The orally active hypoglycemic agents preferably comprise imidazolines,sulphonylureas, biguanides, meglitinides, oxadiazolidinediones,thiazolidinediones, insulin sensitizers, insulin secretagogues, such asglimepiride, α-glucosidase inhibitors, agents acting on theATP-dependent potassium channel of the β-cells for example potassiumchannel openers such as those disclosed in WO 97/26265, WO 99/03861 andWO 00/37474 (Novo Nordisk A/S), or mitiglinide, or a potassium channelblocker, such as BTS-67582, nateglinide, glucagon antagonists such asthose disclosed in WO 99/01423 and WO 00/39088 (Novo Nordisk A/S andAgouron Pharmaceuticals, Inc.), GLP-1 antagonists, DPP-IV (dipeptidylpeptidase-IV) inhibitors, PTPase (protein tyrosine phosphatase)inhibitors, inhibitors of hepatic enzymes involved in stimulation ofgluconeogenesis and/or glycogenolysis, glucose uptake modulators,activators of glucokinase (GK) such as those disclosed in WO 00/58293,WO 01/44216, WO 01/83465, WO 01/83478, WO 01/85706, WO 01/85707, and WO02/08209 (Hoffman-La Roche) or those disclosed in WO 03/00262, WO03/00267 and WO 03/15774 (AstraZeneca), GSK-3 (glycogen synthasekinase-3) inhibitors, compounds modifying the lipid metabolism such asantilipidemics agents such as HMG CoA inhibitors (statins), compoundslowering food intake, PPAR (Peroxisome proliferator-activated receptor)ligands including the PPAR-alpha, PPAR-gamma and PPAR-delta subtypes,and RXR (retinoid X receptor) agonists, such as ALRT-268, LG-1268 orLG-1069.

In another embodiment, the present compounds are administered incombination with insulin or an insulin analogue or derivative, such asN^(εB29)-tetradecanoyl des (B30) human insulin, Asp^(B28) human insulin,Lys^(B28) ProB²⁹ human insulin, Lantus®, or a mix-preparation comprisingone or more of these.

In a further embodiment of the invention the present compounds areadministered in combination with a sulphonylurea such as glibenclamide,glipizide, tolbautamide, chloropamidem, tolazamide, glimepride,glicazide and glyburide.

In another embodiment of the invention the present compounds areadministered in combination with a biguanide, for example, metformin.

In yet another embodiment of the invention the present compounds areadministered in combination with a meglitinide, for example, repaglinideor nateglinide.

In still another embodiment of the invention the present compounds areadministered in combination with a thiazolidinedione insulin sensitizer,for example, troglitazone, ciglitazone, pioglitazone, rosiglitazone,isaglitazone, darglitazone, englitazone, CS-011/CI-1037 or T 174 or thecompounds disclosed in WO 97/41097, WO 97/41119, WO 97/41120, WO00/41121 and WO 98/45292 (Dr. Reddy's Research Foundation).

In still another embodiment of the invention the present compounds maybe administered in combination with an insulin sensitizer, for example,such as GI 262570, YM-440, MCC-555, JTT-501, AR-H039242, KRP-297,GW-409544, CRE-16336, AR-H049020, LY510929, MBX-102, CLX-0940, GW-501516or the compounds disclosed in WO 99/19313, WO 00/50414, WO 00/63191, WO00/63192, WO 00/63193 such as ragaglitazar (NN 622 or (−)DRF 2725) (Dr.Reddy's Research Foundation) and WO 00/23425, WO 00/23415, WO 00/23451,WO 00/23445, WO 00/23417, WO 00/23416, WO 00/63153, WO 63196, WO00/63209, WO 00/63190 and WO 00/63189 (Novo Nordisk A/S).

In a further embodiment of the invention the present compounds areadministered in combination with an α-glucosidase inhibitor, forexample, voglibose, emiglitate, miglitol or acarbose.

In another embodiment of the invention the present compounds areadministered in combination with an agent acting on the ATP-dependentpotassium channel of the β-cells, for example, tolbutamide,glibenclamide, glipizide, glicazide, BTS-67582 or repaglinide.

In yet another embodiment of the invention the present compounds may beadministered in combination with nateglinide.

In still another embodiment of the invention the present compounds areadministered in combination with an antilipidemic agent orantihyperlipidemic agent for example cholestyramine, colestipol,clofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin,pitavastatin, rosuvastatin, probucol, dextrothyroxine, fenofibrate oratorvastin.

In still another embodiment of the invention the present compounds areadministered in combination with compounds lowering food intake.

In another embodiment of the invention, the present compounds areadministered in combination with more than one of the above-mentionedcompounds for example in combination with metformin and a sulphonylureasuch as glyburide; a sulphonylurea and acarbose; nateglinide andmetformin; repaglinide and metformin, acarbose and metformin; asulfonylurea, metformin and troglitazone; insulin and a sulfonylurea;insulin and metformin; insulin, metformin and a sulfonylurea; insulinand troglitazone; insulin and lovastatin; etc.

General terms used in the description of compounds herein described beartheir usual meanings.

As used herein, the terms “(C₁-C₃)alkyl”, “(C₁-C₄)alkyl” or“(C₁-C₆)alkyl” refer to straight-chain or branched-chain saturatedaliphatic groups of the indicated number of carbon atoms, such asmethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,t-butyl, and the like. The term “(C₁-C₆)alkoxy” represents a C₁-C₆ alkylgroup attached through an oxygen and include moieties such as, forexample, methoxy, ethoxy, n-propoxy, isopropoxy, and the like. The term“halogen” refers to fluoro, chloro, bromo, and iodo. The term “(C₃-C₈)cycloalkyl” refers to a saturated or partially saturated carbocycle ringof from 3 to 8 carbon atoms, typically 3 to 7 carbon atoms. Examples of(C₃-C₈) cycloalkyl include but are not limited to cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.

The term “optionally substituted,” or “optional substituents,” as usedherein, means that the groups in question are either unsubstituted orsubstituted with one or more of the substituents specified. When thegroups in question are substituted with more than one substituent, thesubstituents may be the same or different. Furthermore, when using theterms “independently,” “independently are,” and “independently selectedfrom” mean that the groups in question may be the same or different.Certain of the herein defined terms may occur more than once in thestructural formulae, and upon such occurrence each term shall be definedindependently of the other.

It is understood that guinea pigs, dogs, cats, rats, mice, hamsters, andprimates, including humans, are examples of patients within the scope ofthe meaning of the term “patient”. Preferred patients include humans.The term “patient” includes livestock animals. Livestock animals areanimals raised for food production. Ruminants or “cud-chewing” animalssuch as cows, bulls, heifers, steers, sheep, buffalo, bison, goats andantelopes are examples of livestock. Other examples of livestock includepigs and avians (poultry) such as chickens, ducks, turkeys and geese.The patient to be treated is preferably a mammal, in particular a humanbeing.

The terms “treatment”, “treating” and “treat”, as used herein, includetheir generally accepted meanings, i.e., the management and care of apatient for the purpose of preventing, reducing the risk in incurring ordeveloping a given condition or disease, prohibiting, restraining,alleviating, ameliorating, slowing, stopping, delaying, or reversing theprogression or severity, and holding in check and/or treating existingcharacteristics, of a disease, disorder, or pathological condition,described herein, including the alleviation or relief of symptoms orcomplications, or the cure or elimination of the disease, disorder, orcondition. The present method includes both medical therapeutic and/orprophylactic treatment, as appropriate.

As used herein, the term “therapeutically effective amount” means anamount of compound of the present invention that is capable ofalleviating the symptoms of the various pathological conditions hereindescribed. The specific dose of a compound administered according tothis invention will, of course, be determined by the particularcircumstances surrounding the case including, for example, the compoundadministered, the route of administration, the state of being of thepatient, and the pathological condition being treated.

“Composition” means a pharmaceutical composition and is intended toencompass a pharmaceutical product comprising the active ingredient(s)including compound(s) of Formula I, and the inert ingredient(s) thatmake up the carrier. Accordingly, the pharmaceutical compositions of thepresent invention encompass any composition made by admixing a compoundof the present invention and a pharmaceutically acceptable carrier.

The term “substantially pure” refers to pure crystalline form of acompound comprising greater than about 90% of the desired crystallineform, and preferably, greater than about 95% of the desired crystalform.

The term “suitable solvent” refers to any solvent, or mixture ofsolvents, inert to the ongoing reaction that sufficiently solubilizesthe reactants to afford a medium within which to effect the desiredreaction.

The term “unit dosage form” means physically discrete units suitable asunitary dosages for human subjects and other non-human animals, eachunit containing a predetermined quantity of active material calculatedto produce the desired therapeutic effect, in association with asuitable pharmaceutical carrier.

The compounds of the present invention may have one or more chiralcenters and may exist in a variety of stereoisomeric configurations. Asa consequence of these chiral centers the compounds of the presentinvention can occur as racemates, as individual enantiomers or mixturesof enantiomers, as well as diastereomers and mixtures of diastereomers.All such racemates, enantiomers, diastereomers and mixtures are withinthe scope of the present invention, whether pure, partially purified, orunpurified mixtures. For the examples provided herein, when a moleculewhich contains a chiral center or centers of known configuration ispresented, its stereochemistry is designated in the name and in thestructural representation of the molecule. If the stereochemistry isunknown or undefined its stereochemistry is not designated in the nameor in the structural representation of the molecule. Embodiments of theinvention include the Examples provided herein, and although the Exampleprovided may be of one chiral or conformational form, or a salt thereof,further embodiments of the invention include all other steroisomeric andor conformational forms of the examples described, as well aspharmaceutically acceptable salts thereof. These embodiments include anyisolated enantiomers, diastereomers, and or conformers of thesestructures, as well as any mixtures containing more than one form.

Furthermore, when a double bond or a fully or partially saturated ringsystem or more than one center of asymmetry or a bond with restrictedrotatability is present in the molecule diastereomers may be formed. Itis intended that any diastereomers, as separated, pure or partiallypurified diastereomers or mixtures thereof are included within the scopeof the invention. Furthermore, some of the compounds of the presentinvention may exist in different tautomeric forms and it is intendedthat any tautomeric forms which the compounds are able to form areincluded within the scope of the present invention.

The term “enantiomeric enrichment” as used herein refers to the increasein the amount of one enantiomer as compared to the other. A convenientmethod of expressing the enantiomeric enrichment achieved is the conceptof enantiomeric excess, or ee which is found using the followingequation:

${ee} = {\frac{E^{1} - E^{2}}{E^{1} + E^{2}} \times 100}$

wherein E¹ is the amount of the first enantiomer and E² is the amount ofthe second enantiomer. Thus, if the initial ratio of the two enantiomersis 50:50, such as is present in a racemic mixture, and an enantiomericenrichment sufficient to produce a final ratio of 70:30 is achieved, theee with respect to the first enantiomer is 40%. However, if the finalratio is 90:10, the ee with respect to the first enantiomer is 80%. Anee of greater than 90% is preferred, an ee of greater than 95% is mostpreferred and an ee of greater than 99% is most especially preferred.Enantiomeric enrichment is readily determined by one of ordinary skillin the art using standard techniques and procedures, such as gas or highperformance liquid chromatography with a chiral column. Choice of theappropriate chiral column, eluent and conditions necessary to effectseparation of the enantiomeric pair is well within the knowledge of oneof ordinary skill in the art. In addition, the specific stereoisomersand enantiomers of compounds of formula I can be prepared by one ofordinary skill in the art utilizing well known techniques and processes,such as those disclosed by J. Jacques, et al., “Enantiomers, Racemates,and Resolutions”, John Wiley and Sons, Inc., 1981, and E. L. Eliel andS. H. Wilen, “Stereochemistry of Organic Compounds”, (Wiley-Interscience1994), and European Patent Application No. EP-A-838448, published Apr.29, 1998. Examples of resolutions include recrystallization techniquesor chiral chromatography.

The compounds of Formula I, can be prepared by one of ordinary skill inthe art following a variety of procedures, some of which are illustratedin the procedures and schemes set forth below. The particular order ofsteps required to produce the compounds of Formula I is dependent uponthe particular compound to being synthesized, the starting compound, andthe relative lability of the substituted moieties. The reagents orstarting materials are readily available to one of skill in the art, andto the extent not commercially available, are readily synthesized by oneof ordinary skill in the art following standard procedures commonlyemployed in the art, along with the various procedures and schemes setforth below.

The following Schemes, Preparations, Examples and Procedures areprovided to better elucidate the practice of the present invention andshould not be interpreted in any way as to limit the scope of the same.Those skilled in the art will recognize that various modifications maybe made while not departing from the spirit and scope of the invention.All publications mentioned in the specification are indicative of thelevel of those skilled in the art to which this invention pertains.

The optimal time for performing the reactions of the Schemes,Preparations, Examples and Procedures can be determined by monitoringthe progress of the reaction via conventional chromatographictechniques. Furthermore, it is preferred to conduct the reactions of theinvention under an inert atmosphere, such as, for example, argon,nitrogen. Choice of solvent is generally not critical so long as thesolvent employed is inert to the ongoing reaction and sufficientlysolubilizes the reactants to effect the desired reaction. The compoundsare preferably isolated and purified before their use in subsequentreactions. Some compounds may crystallize out of the reaction solutionduring their formation and then collected by filtration, or the reactionsolvent may be removed by extraction, evaporation, or decantation. Theintermediates and final products of Formula I may be further purified,if desired by common techniques such as recrystallization orchromatography over solid supports such as silica gel or alumina.

The skilled artisan will appreciate that not all substituents arecompatible with all reaction conditions. These compounds may beprotected or modified at a convenient point in the synthesis by methodswell known in the art.

The terms and abbreviations used in the instant Schemes, Preparations,Examples and Procedures have their normal meanings unless otherwisedesignated. For example, as used herein, the following terms have themeanings indicated: “psi” refers to pounds per square inch; “TLC” refersto thin layer chromatography; “HPLC” refers to high performance liquidchromatography; “R_(f)” refers to retention factor; “R_(t)” refers toretention time; “δ” refers to part per million down-field fromtetramethylsilane; “MS” refers to mass spectrometry, Observed Massindicates [M+H] unless indicated otherwise. “MS (APCi) refers toatmospheric pressure chemical ionization mass spectrometry, “UV” refersto ultraviolet spectrometry, “¹H NMR” refers to proton nuclear magneticresonance spectrometry. “LCMS” refers to liquid chromatography-massspectrometry, “GC/MS” refers to gas chromatography/mass spectrometry.“IR” refers to infra red spectrometry, and the absorption maxima listedfor the IR spectra are only those of interest and not all of the maximaobserved. “RT” refers to room temperature.

“THF” refers to tetrahydrofuran, “LAH” refers to lithium aluminumhydride, “LDA” refers to lithium diisopropylamide, “DMSO” refers todimethylsulfoxide, “DMF” refers to dimethylforamide, “EtOAc” refers toethyl acetate, “Pd—C” refers to palladium on carbon, “DCM” refers todichloromethane, “DMAP” refers to dimethylaminopyridine, “LiHMDS” refersto Lithium Hexamethyldisilisane, “TFA” refers to trifluoroacetic acid,“EDAC” refers to N-Ethyl-N′-(3-dimethylaminopropyl)carbodiimidehydrochloride, “HOBT” refers to 1-Hydroxy benzotriazole, “Bn-9-BBN”refers to Benzyl-9-borabicyclo [3.3.1]nonane, “Pd(dppf)Cl₂” refers to[1,1′-Bis(diphenylphosphino)-ferrocene)dichloropalladium(II), “EDCI”refers to N-Ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride,“DBU” refers to 1,8-Diazabicyclo[5.4.0]undecene-7, “TBSCl” refers totert-butyl-dimethyl-silanyloxymethyl chloride, “NBS” refers toN-Bromosuccinimide, “TsOH” refers to p-toluenesulfonic acid, “DCE”refers to dichloroethane, “DAST” refers to (Diethylamino)sulfurtrifluoride, “EA/H” refers to ethyl acetate/hexanes mixture, “Pd₂(dba)₃”refers to Bis(dibenzylideneacetone)palladium, “BINAP” refers to2,2′-Bis(diphenylphospino-1,1′-binaphthalene, “NMP” refers toN-Methylpyrrollidine, “TMSCN” refers to Trimethylsilyl cyanide, “TBAF”refers to Tetrabutylammonium fluoride, “Tf₂O” refers totrifluoromethanesulfonic anhydride, “TBSO” refers totert-butyl-dimethyl-silanyloxy, “OTf” refers totrifluoromethanesulfonate, MeTi(Oi-Pr)₃ refers to methyltitaniumtriisopropoxide, “BBr₃” refers to boron tribromide, “PBr₃” refers tophosphorous tribromide, “Pd(PPh₃)₄” refers totetrakis(triphenylphoshine)palladium (0), “OAc” refers to acetate, “DME”refers to dimethylethane, “Et₂O” refers to diethyl ether, “(Ph₃P)₄Pd”refers to tetrakis(triphenylphoshine)palladium (0), “DMFDMA” refers toN,N-dimethylformamide dimethyl acetal, “Et₃N” refers to triethylamine,“tBu” refers to t-butyl, “DIPEA” refers to diisopropylethyl amine, “EDC”refers to -(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride,“HOAc” refers to acetic acid, “boc” refers to t-butoxycarbonyl. In astructure, “Ph” refers to phenyl, “Me” refers to methyl, “Et” refers toethyl, “Bn” refers to benzyl, “MeOH” refers to methanol, “OTf” refers totrifluoromethanesulfonate, “TIPSO” refers to triisopropylsilanyloxy,“TBSO” refers to tert-butyl-dimethyl-silanyloxy.

The Examples provided herein are illustrative of the invention claimedherein and are not intended to limit the scope of the claimed inventionin any way. The preparations and examples are named using AutoNom 2.2 inChemDraw Ultra, or AutoNom 2000 in MDL ISIS/Draw version 2.5 SP1 fromMDL Information Systems, Inc., or are provided by Chemical AbstractsServices.

A Varian INOVA 400 MHz spectrometer is used to obtain ¹H NMR Specta thein the solvent indicated. An Agilent HP 1100 instrument equipped with aMass Spectrometer (Agilent MSD SL) is used to obtain LCMS. A WatersXterra C18 (2.1×50 mm, 3.5 micron) is used as stationary phase and astandard method is a gradient of 5-100% acetonitrile/methanol (50:50)with 0.2% ammonium formate over 3.5 minutes then held at 100% B for 0.5minutes at a column temperature of 50° C. and a flow rate of 1.0 mL/min.Another standard method is a gradient of 5-100% acetonitrile/methanol(50:50) with 0.2% ammonium formate over 7.0 minutes then held at 100% Bfor 1.0 minutes at a column temperature of 50° C. and a flow rate of 1.0mL/min. Additional MS analysis via Agilent MSD (loop machine) isstandard Flow injection Analysis (FIA), no column is present and flow is0.5 ml/min of 80% MeOH with 6.5 mM Ammonium Acetate for 30 secs runtime.

In Scheme A, an optionally substituted phenol (1) is protected (e.g,with TBSCl) to form compound 2, and then compound 2 is converted to thealdehyde (3). Compound 3 is reacted with a compound containing aprotecting group (Pg) and leaving group (Lg) to give the ether compound4. Pg can be —CH₃ or —CH₂-phenyl and Lg can be mesylate or halo.Preferably, the Lg-Pg compound is I—CH₃ or Br—CH₂-phenyl. The aldehydeis reduced to form the alcohol (5) and then converted to compound 6.Preferably, compound 5 is halogenated with PBr₃ to give the2-bromo-methyl compound.

Protection and deprotection of the compounds to form compounds offormula I and others are well known to the skilled artisan and aredescribed in the literature. (For example, see: Greene and Wuts,Protective Groups in Organic Synthesis, Third Edition, John Wiley andSons Inc., 1999).

In Scheme B, a compound of formula Ia is formed by first reactingcompound 7 with compound 6 (Scheme A) to form compound 8. Then, thedimethoxy compound 8 is converted to the aldehyde (9). Compound 9 isreacted with the tetrahydro-benzoimidazol-5-ylamine (10) to form theracemic lactam (11) which is then converted to the compound 13. Compound13 is deprotected to form the phenol (14). Compound 14 is converted intothe pair of isomers (15) by reacting with trifluoromethanesulfonicanhydride. A coupling reaction is performed on 15 using a boronic acidreagent (R⁴—B(OH)₂) and a catalyst, such astetrakis(triphenylphosphene)palladium(0).

Scheme C shows the stereo selective synthesis to form the intermediatecompound 18. Compound 16 is formed by acylating commercially available(R)-4-benzyl-oxazolidin-2-one with 4-pentenoyl chloride. It is thenalkylated with an optionally substituted compound 6 (see Scheme A) togive compound of 17. Compound 17 is oxidized to form the aldehydeintermediate compound 18 using ozone and triphenylphosphine or osmiumtetroxide and an oxidant such as sodium metaperiodate.

In Scheme D, the intermediate (18) is converted to the lactam compound20 which is in the “R” configuration. A deprotection is performed togive compound 21 which is then trfliated (trifluoromethanesulfonicanhydride) to form the isomer pair (22). A coupling reaction isperformed on 22 using a boronic acid reagent (R⁴—B(OH)₂) and a catalyst,such as tetrakis(triphenylphosphene)palladium(0).

In Scheme E, nitrobenzimidazol (23) is hydrogenated to form racemic4,5,6,7-tetrahydro-3H-benzoimidazol-5-ylamine (24). Then, compound 25 isresolved by fractional crystallization using dibenzoyl-D-tartarate.(Siegfried Schwarz and Walter Schunack; Arch. Pharm. vol 312, pp933-939, year 1979).

In Scheme F, the intermediate (18) is reacted with resolved compound 25(Scheme E) to form the lactam compound 26 which is in the “R”configuration. A deprotection is performed to give compound 27 which isthen trfliated (trifluoromethanesulfonic anhydride) to form the isomerpair (28). A coupling reaction is performed on 28 using a boronic acidreagent (R⁴—B(OH)₂) and a catalyst, such astetrakis(triphenylphosphene)palladium(0).

Preparation 1 2,6-dichloro-4-hydroxy-benzaldehyde

Dissolve 3,5 dichlorophenol (1 kg, 6.13 mol) in 3 L dimethylformamide(DMF) and cool to 0° C. Add imidazole (918.74 g, 6.75 mol), followed bytertbutyldimethylsilyl chloride (1017.13 g, 6.75 mol). Warm the mixtureto room temperature and stir for 15 minutes. Pour into water (6 L) andextract with ether (4 L). Wash the organic layer with water 2 times, 10%aqueous lithium chloride solution then brine before drying over sodiumsulfate. Filter and concentrate under vacuum to obtaintert-butyl-(3,5-dichloro-phenoxy)-dimethyl-silane (1700 g) as an oil.

Dissolve tert-butyl-(3,5-dichloro-phenoxy)-dimethyl-silane (425 g, 1.5mol) in 4 L dry tetrahydrofuran and cool to −68° C. Slowly add 1.1equivalents of sec-butyl lithium (103.1 g, 1.61 mol) at −68° C. (˜1.75hr). After addition is complete stir the reaction at −70° C. for 30 min.Add dimethylformamide (168.5 g, 2.3 mol) and stir the reaction at −70°C. for 1 hr. Add 1 M hydrochloric acid in water (3.5 L) and allow thereaction to warm to room temperature.

Pour the reaction mixture into ether (5 L), wash with water then brine.Dry over sodium sulfate and concentrate under vacuum to an orange solid.Triturate with cold dichloromethane and filter to recover 250 g (80%)pale yellow solid.

Preparation 2 2,6-dichloro-4-methoxy-benzaldehyde

Combine 2,6-dichloro-4-hydroxy-benzaldehyde (120 g, 628.24 mmol) andpotassium carbonate (173.65 g, 1256.5 mmol) in 900 mL dimethylformamideand treat with iodomethane (107 g, 753.9 mmol). Stir the reaction atroom temperature for 3 hours. Filter off solids and pour into 6 L ofwater. Filter solids, wash several times with water, air dry anddissolve in ethyl acetate. Wash with water, followed by brine and thendry over sodium sulfate. Filter and concentrate under vacuum to 100 mLvolume, at which point, solids start to crash out. Filter thenconcentrate down the filtrate to yield a second crop. Wash with hexane,combine all solids and vacuum dry to yield 112.3 g of off-white, solid:¹H NMR (400 MHz, CDCl₃) δ 10.41 (s, 1H), 6.90 (s, 2H), 3.87 (s, 3H).

Preparation 3 2,6-dichloro-4-benzyloxy-benzaldehyde

Treat a mixture of 2,6-dichloro-4-hydroxy-benzaldehyde (250 g, 1.3 mol)and potassium carbonate (361.8 g, 2.62 mol) in 2 L dimethylformamidewith benzyl bromide (268.64 g, 1.57 mol). Stir the reaction at roomtemperature for 1 hour. Filter off solids and pour into 12 L of water.Filter off solid, wash several times with water, air dry and dissolve inethyl acetate. Dry over magnesium sulfate, filter and concentrate undervacuum to ˜1.5 L. Allow to sit overnight then filter. Wash solid withminimal amount of hexane and vacuum dry. Concentrate the filtrate undervacuum and triturate with hexane to yield a second crop of product whichwhen combined with the first crop equals 245 g white crystals. Repeat toobtain a 3rd crop of 80 g as a light-tan powder (88% overall yield): ¹HNMR (400 MHz, DMSO-d6) δ 10.26 (s, 1H), 7.43 (m, 5H), 7.28 (s, 2H), 5.25(s, 2H).

Preparation 4 (2,6-dichloro-4-methoxy-phenyl)-methanol

Suspend 2,6-dichloro-4-methoxy-benzaldehyde (112 g, 546 mmol) in 1500 mLethanol and cool in an ice bath to 7° C. Add sodium borohydride (20.67,546 mmol) portionwise to obtain a solution. Remove the ice bath and stirfor 2 hours. Carefully add reaction mixture to saturated ammoniumchloride solution (˜4 L) and stir until fully quenched. Extract withdichloromethane (3×1 L) and dry the combined organic extracts oversodium sulfate. Filter and concentrate under vacuum to yield 113 g of alight-tan solid: ¹H NMR (400 MHz, CDCl₃) δ 6.86 (s, 2H), 4.86 (s, 2H),3.78 (s, 3H), 2.07 (s, 1H).

Preparation 5 (2,6-dichloro-4-benzyloxy-phenyl)-methanol

Prepare the title compound essentially as prepared by the method ofPreparation 4. NMR (DMSO-d₆) δ 7.38 (m, 4H), 7.33 (m, 1H), 7.12 (s, 2H),5.14 (s, 2H), 5.05 (t, 1H), 4.59 (d, 2H).

Preparation 6 2-bromomethyl-1,3-dichloro-5-methoxy-benzene

Dissolve (2,6-dichloro-4-methoxy-phenyl)-methanol (113 g, 545.76 mmol)in 1200 mL dry THF and cool to 0 deg under nitrogen. Add PBr₃ (59.1 g,218.3 mmol) under nitrogen and stir at 0° C. for 30 minutes. Pour intosaturated aqueous NaHCO₃ and extract with EtOAc. Dry and concentrateunder vacuum to obtain 129.4 g product as an off-white solid. NMR(CDCl₃) δ 6.88 (s, 2H), 4.73 (s, 2H), 3.79 (s, 3H).

Preparation 7 2-bromomethyl-1,3-dichloro-5-benzyloxy-benzene

Prepare the title compound essentially as prepared by the method ofPreparation 6 in an 89% yield. ES MS (m/z): 347 (M+1).

Preparation 8 4,5,6,7-tetrahydro-3H-benzoimidazol-5-ylaminedihydrochloride

Add 5% Rh/C (5.215 g) to a 500 ml glass Parr bottle. Purge the bottlewith nitrogen and wet the 5% Rh/C with 3 N HCl (50 ml). Then add6-nitro-1H-benzoimidazole (10.354 g, 0.0635 mol) and 3N HCl (100 ml) tothe purged bottle. Seal the Parr bottle and purge the reaction vesselwith nitrogen (3×) and with hydrogen (3×). Then pressurize the reactionmixture with hydrogen (60 psig), seal the vessel but add hydrogen asneeded to maintain 60 psig, agitate the reaction and heat to 80° C.Continue the reaction for 24 hours then turn off the heat and allow thereaction mixture to cool to ambient temperature. Vent the excesshydrogen from the vessel, purge the vessel with nitrogen (3×) and filterthe reaction mixture to remove the 5% Rh/C catalyst. The filtrate isconcentrated to dryness on a rotary evaporator and then under highvacuum. Dissolve the solid residue in 20 mL of methanol, heat toapproximately 60° C. and add additional methanol (approximately up to 10mL or as needed) to dissolve the residue completely. Cool the solutionto room temperature and add ether (40 mL). A white solid separates,filter and dry under high vacuum to give the product (8.gm).

¹H NMR (D₂O): δ 1.80-2.11 (1H), 2.09-2.22 (1H), 2.60-2.79 (4H),3.01-3.15 (1H), 3.61-3.75 (1H), 8.41 (1H).

Preparation 92-(4-benzyloxy-2,6-dichloro-benzyl)-2-(2,2-dimethoxy-ethyl)-malonic aciddiethyl ester

Cool 2-(2,2-Dimethoxy-ethyl)-malonic acid diethyl ester (4.5 g, 16.3mmol) in 50 mL THF to −78° C. and add lithium hexamethylsilane amide (1M, 17 mL) drop wise. After 15 min, add5-benzyloxy-2-bromomethyl-1,3-dichloro-benzene (17.9 mmol 6.2 g) in 10mL THF. Warm this mixture to ambient temperature, acidify with 1 N HCl,and extract with ethyl acetate. Concentrate the organics and purify bynormal phase column chromatography to afford the title compound as awhite solid (7.0 g, 80%).

Preparation 102-(4-benzyloxy-2,6-dichloro-benzyl)-2-(2-oxo-ethyl)-malonic acid diethylester

To a solution of2-(4-benzyloxy-2,6-dichloro-benzyl)-2-(2,2-dimethoxy-ethyl)-malonic aciddiethyl ester (10.0 g, 18.5 mmol) (Preparation 9) in 95 mL of acetone,add 10 ml of formic acid. After 24 h, concentrate the reaction to2-(4-benzyloxy-2,6-dichloro-benzyl)-2-(2-oxo-ethyl)-malonic acid diethylester as yellow oil product (6.7 g, 80%).

Preparation 113-(4-benzyloxy-2,6-dichloro-benzyl)-2-oxo-1-(4,5,6,7-tetrahydro-3H-benzoimidazol-5-yl)-pyrrolidine-3-carboxylicacid ethyl ester

Add sodium cyanoborohydride (3.6 g, 57.4 mmol) portion wise to asolution of 2-(4-benzyloxy-2,6-dichloro-benzyl)-2-(2-oxo-ethyl)-malonicacid diethyl ester (6.7 g, 14.4 mmol) (Preparation 10) and4,5,6,7-tetrahydro-3H-benzoimidazol-5-ylamine dihydrochloride salt (6.0g, 28.7 mmol) (Preparation 1) in 70 ml of Methanol. After 3 h, add 4 mlof acetic acid and warm to 60° C. for 16 h. Most of the Methanol isremoved via rotovap. Quench the resulting mixture with saturatedbicarbonate and extract with ethyl acetate. Dry extracts over sodiumsulfate, concentrate, and purify by normal phase column chromatography(0-10% methanol in ethyl acetate) to afford3-(4-Benzyloxy-2,6-dichloro-benzyl)-2-oxo-1-(4,5,6,7-tetrahydro-3H-benzoimidazol-5-yl)-pyrrolidine-3-carboxylicacid ethyl ester as a white solid (3 g).

Preparation 123-(4-Benzyloxy-2,6-dichloro-benzyl)-1-(4,5,6,7-tetrahydro-3H-benzoimidazol-5-yl)-pyrrolidin-2-one

Dissolve3-(4-Benzyloxy-2,6-dichloro-benzyl)-2-oxo-1-(4,5,6,7-tetrahydro-3H-benzoimidazol-5-yl)-pyrrolidine-3-carboxylicacid ethyl ester (3 g, 5.5 mmol) (Preparation 11) in 10 ml of Methanoland then add 10 ml of 2 N NaOH. Stir this mixture for 16 h, concentrate,and then add dioxane and acetic acid to obtain3-(4-Benzyloxy-2,6-dichloro-benzyl)-2-oxo-1-(4,5,6,7-tetrahydro-3H-benzoimidazol-5-yl)-pyrrolidine-3-carboxylicacid which is not isolated. Reflux the mixture overnight, quench withwater and extract with ethyl acetate. Wash the extracts with saturatedbicarbonate and concentrate to3-(4-Benzyloxy-2,6-dichloro-benzyl)-1-(4,5,6,7-tetrahydro-3H-benzoimidazol-5-yl)-pyrrolidin-2-oneproduct (2.6 g). MS: m/z (M+1)=470.

Preparation 133-(2,6-Dichloro-4-hydroxy-benzyl)-1-(4,5,6,7-tetrahydro-1H-benzoimidazol-5-yl)-pyrrolidin-2-one

Add palladium hydroxide to a nitrogen purged solution of3-(4-Benzyloxy-2,6-dichloro-benzyl)-1-(4,5,6,7-tetrahydro-1H-benzoimidazol-5-yl)-pyrrolidin-2-one(4.3 g, 9.2 mmol) (Preparation 12) in 50 ml of ethyl acetate and 15 mlof methanol. Add about 22 psi of pressurized nitrogen and stir for 16 h.Filter this mixture and concentrate to afford3-(2,6-Dichloro-4-hydroxy-benzyl)-1-(4,5,6,7-tetrahydro-1H-benzoimidazol-5-yl)-pyrrolidin-2-oneas solid product (2 g). MS: m/z (M+1)=380.

Preparation 14 Trifluoro-methanesulfonic acid3,5-dichloro-4-[2-oxo-1-(3-trifluoromethanesulfonyl-4,5,6,7-tetrahydro-3H-benzimidazol-5-yl)-pyrrolidin-3-ylmethyl]-phenyland trifluoro-methanesulfonic acid3,5-dichloro-4-[2-oxo-1-(1-trifluoromethanesulfonyl-4,5,6,7-tetrahydro-3H-benzimidazol-5-yl)-pyrrolidin-3-ylmethyl]-phenylesters

Take up3-(2,6-dichloro-4-hydroxy-benzyl)-1-(4,5,6,7-tetrahydro-3H-benzimidazol-5-yl)-pyrrolidin-2-one(0.5 g) (Preparation 13) in DCM (2 mL) and pyridine (2 mL). Cool thesolution to 0° C. in ice bath and add trifluoromethanesulfonic anhydride(0.5 mL) dropwise with stirring. The reaction mixture is then leftstanding −30° C. for overnight in a freezer. Dilute the reaction mixturewith ethyl acetate (50 mL). Wash with 1 M aqueous HCl (2×50 mL), brine(50 mL). Dry the ethyl acetate layer over sodium sulfate and concentrateon a rotary evaporator. Drying the residue under high vacuum givesmixtures of trifluoro-methanesulfonic acid3,5-dichloro-4-[2-oxo-1-(3-trifluoromethanesulfonyl-4,5,6,7-tetrahydro-3H-benzimidazol-5-yl)-pyrrolidin-3-ylmethyl]-phenyland trifluoro-methanesulfonic acid3,5-dichloro-4-[2-oxo-1-(1-trifluoromethanesulfonyl-4,5,6,7-tetrahydro-3H-benzimidazol-5-yl)-pyrrolidin-3-ylmethyl]-phenylesters as a yellow foamy solid (650 mg). Proceed to the next stepwithout purification. MS: m/z (M+1)=643.

Preparation 15 (R)-4-benzyl-3-pent-4-enoyl-oxazolidin-2-one

Flush with nitrogen a 12 L 3-neck round bottom flask equipped with amechanical stirrer, internal temperature probe/N₂ inlet, and 1 Laddition funnel for 20 min and then add (R)-4-benzyl-2-oxazolidinone(250 g, 1.41 mol). Dilute with tetrahydrofuran (THF) (1.8 L) and cool ina dry ice/acetone bath until the internal temperature is −74° C.Transfer a 1.6 M hexanes solution of n-butyllithium (970 mL, 1.552 mol)to the addition funnel via cannula, and add to the oxazolidinonesolution at a rate such that the internal temperature does not reachabove −65° C. After the addition is complete, allow the reaction to stirin the cooling bath 30 min. Transfer 4-pentenoyl chloride (175 mL, 1.585mol) to the addition funnel and add dropwise to the anion solution overa 25 min period. Stir the reaction for 45 min in the cooling bath.Remove the cooling bath and stir the reaction 18 hr as it slowly reachesroom temperature. Dilute the mixture with 1 N aqueous hydrochloric acid(1.5 L) and diethyl ether (1 L). Separate the layers and wash theorganic phase with water (2×1 L) then brine (1 L). Extract the combinedaqueous washes with ether (1 L). Dry the combined organic phases overanhydrous magnesium sulfate, filter, and concentrate to 390 g of a lighttan oil. Purify this material by silica gel chromatography usinghexanes:ethyl acetate to obtain 345 g (94.5%) of a clear, yellow oil.

Preparation 16(R)-4-Benzyl-3-[(S)-2-(4-benzyloxy-2,6-dichloro-benzyl)-pent-4-enoyl]-oxazolidin-2-one

Stir a mixture of (R)-4-benzyl-3-pent-4-enoyl-oxazolidin-2-one (345 g,1.33 mol) and THF (1.8 L) in a 12 L 3-neck round bottom flask, withinternal temperature probe/nitrogen inlet and addition funnel, under anitrogen atmosphere and cool to −75° C. Transfer 1 M LiHMDS (1.6 L) tothe addition funnel and add at a rate such that the internal temperaturedoes not reach above −60° C. After the addition is complete, allow thereaction to stir at −25° C. for 30 min then cool to about −60° C. Atthis point add solid 2-bromomethyl-1,3-dichloro-5-benzyloxy-benzeneportionwise over 5 min. After the addition is complete, transfer thereaction vessel to a −10° C. acetone bath and maintain the internalreaction temperature below 10° C. for 1 hr. Cool the mixture to 0° C.then quench with 2 L aqueous 1 N hydrochloric acid. Transfer the mixtureto a 22 L separatory funnel and dilute with 2.5 L water and 2 L ether.Separate the layers and extract the aqueous layer with ether. Dry thecombined organic phase over anhydrous magnesium sulfate, filter andconcentrate to 800 g of a thick oil. Purify by silica gel chromatographyusing hexanes:ethyl acetate to obtain 597 g, (86%) of a colorless oil.

Preparation 17(R)-4-((R)-4-Benzyl-2-oxo-oxazolidin-3-yl)-3-(4-benzyloxy-2,6-dichloro-benzyl)-4-oxo-butyraldehyde

Cool a mixture of(R)-4-Benzyl-3-[(S)-2-(4-benzyloxy-2,6-dichloro-benzyl)-pent-4-enoyl]-oxazolidin-2-one(100 g, 190.68 mmol) and dichloromethane (800 mL) to −74° C. Bubbleozone, produced via the A-113 ozone generator at a rate of 75%, throughthe reaction via carrier air at a rate of 5 CFM until the solution takeson a blue color (approx 3 hr). Add triphenylphosphine (60 g, 228.8 mmol)as a solution in 200 mL dichloromethane and allow the reaction to stirwhile reaching room temperature over night. Concentrate the solutionunder vacuum and purify by silica gel chromatography using a gradient of20-50% ethyl acetate in hexanes to obtain 82.1 g (82%) of the product asa white foam: MS (m/z): 526 (M+).

Alternate procedure for making(R)-4-((R)-4-Benzyl-2-oxo-oxazolidin-3-yl)-3-(4-benzyloxy-2,6-dichloro-benzyl)-4-oxo-butyraldehyde:

Treat a mixture of(R)-4-Benzyl-3-[(S)-2-(4-benzyloxy-2,6-dichloro-benzyl)-pent-4-enoyl]-oxazolidin-2-one(0.96 g, 1.8 mmol), THF (21 mL) and water (7 mL) with 2.5% osmiumtetroxide in t-butanol (46 mg, 0.18 mmol). Add sodium periodate (1.17 g,5.5 mmol) and stir the reaction 4 hr at room temperature. Quench thereaction with water and extract with ethyl acetate. Wash the organicphase with aqueous 1 N sodium thiosulfate then brine. Dry the organiclayer over magnesium sulfate, filter, and concentrate under vacuum.Purify the crude material by silica gel chromatography usinghexanes:ethyl acetate to elute the pure product. Concentrate thefractions containing product under vacuum to afford 0.46 g (48%) ofdesired product. MS (m/z): 526 (M+).

Preparation 183-[R]-(4-benzyloxy-2,6-dichloro-benzyl)-1-(4,5,6,7-tetrahydro-3H-benzimidazole-3-yl)-pyrrolidin-2-one

Add Preparation 10 (5.25 g) to a suspension ofimidazolocyclohexy-3-amine hydrochloride (2 gm) (Preparation 8) inmethanol (30 mL). Stir the mixture at room temperature for 30 min. Addsodium cyanoborohydride (1 g) and stir the mixture for 2 h. Heat thereaction mixture at 50° C. for 2 h. Dilute the reaction mixture withethyl acetate (50 mL) and wash the mixture with water (50 mL). Dry ethylacetate layer over sodium sulfate and concentrate on rotary evaporatorto give a crude. Purify the crude by silica flash chromatography elutingwith a gradient of 0-5% methanol in DCM to give the product as a mixtureof diastereomers,3-(4-benzyloxy-2,6-dichloro-benzyl)-1-(4,5,6,7-tetrahydro-3H-benzimidazole-3-yl)-pyrrolidin-2-one(4.5 gm). MS: m/z=470 (M+1).

Preparation 193-[R]-(2,6-dichloro-4-hydroxy-benzyl)-1-(4,5,6,7-tetrahydro-3H-benzimidazol-5-yl)-pyrrolidin-2-one

Take up3-(4-benzyloxy-2,6-dichloro-benzyl)-1-(4,5,6,7-tetrahydro-3H-benzimidazole-3-yl)-pyrrolidin-2-one(2.5 g) (Preparation 18) in methanol (50 mL) and ethylacetate (30 mL) ina pressure bottle. Add palladium hydroxide catalyst (500 mg) and stirthe reaction mixture under hydrogen atmosphere (30 psi) at 40° C. forover night. Filter the reaction mixture over celite. Concentratefiltrate to give the product,3-[R]-(2,6-dichloro-4-hydroxy-benzyl)-1-[R/S]-(4,5,6,7-tetrahydro-3H-benzimidazol-5-yl)-pyrrolidin-2-onea white solid (1.6 gm) as mixture. MS: m/z=379 (M+1).

Preparation 20 Trifluoro-methanesulfonic acid3,5-dichloro-4-[2-oxo-1-(3-trifluoromethanesulfonyl-4,5,6,7-tetrahydro-3H-benzimidazol-5-yl)-pyrrolidin-3-[R]-ylmethyl]-phenyland trifluoro-methanesulfonic acid3,5-dichloro-4-[2-oxo-1-(1-trifluoromethanesulfonyl-4,5,6,7-tetrahydro-3H-benzimidazol-5-yl)-pyrrolidin-3-[R]-ylmethyl]-phenylesters (13).

Take up3-[R]-(2,6-dichloro-4-hydroxy-benzyl)-1-(4,5,6,7-tetrahydro-3H-benzimidazol-5-yl)-pyrrolidin-2-one(1.6 g) (Preparation 19) in DCM (20 mL) and pyridine (5 mL). Cool thesolution to −78° C. and add trifluorosulfonic anhydride (3 mL) drop wisewith stirring. The reaction mixture is then left standing for 48 h in afreezer. Dilute the reaction mixture with ethyl acetate (150 mL). Washwith 1 M aqueous HCl (2×50 mL), brine (50 mL). Dry the ethyl acetatelayer over sodium sulfate and concentrate on a rotary evaporator. Dryingthe residue under high vacuum to gives mixtures oftrifluoro-methanesulfonic acid3,5-dichloro-4-[2-oxo-1-(3-trifluoromethanesulfonyl-4,5,6,7-tetrahydro-3H-benzimidazol-5-yl)-pyrrolidin-3-ylmethyl]-phenyland trifluoro-methanesulfonic acid3,5-dichloro-4-[2-oxo-1-(1-trifluoromethanesulfonyl-4,5,6,7-tetrahydrosolid (2.01 g). The mixture is carried on to next step withoutpurification.

MS: m/z (M+1)=643.

Preparations 21 and 22 Chiral purification of3-[R]-(4-benzyloxy-2,6-dichloro-benzyl)-1-(4,5,6,7-tetrahydro-3H-benzimidazole-3-yl)-pyrrolidin-2-one

Purify diastereoisomeric mixture of3-(4-benzyloxy-2,6-dichloro-benzyl)-1-(4,5,6,7-tetrahydro-3H-benzimidazole-3-yl)-pyrrolidin-2-one(2 gm) (Preparation 18) on a Chiralpak AD-H (0.46×15 cm) column elutingwith 60:40:0.2 3A ethanol/heptane/DMEA (Flow=0.6 mL/min.) to give:

Isomer 1 (Preparation 21), Ret time 5.4 min, 922 mg) and

Isomer 2 (Preparation 22), Ret time 7.1 min, 866 mg.

Use Isomer 2 for Preparation 23. Preparation 234,5,6,7-Tetrahydro-3H-benzoimidazol-5-ylamine dibenzoyl-D-tartric acid

(Siegfried Schwarz and Walter Schunack; Arch. Pharm. vol 312, pp933-939, year 1979). Dissolve4,5,6,7-Tetrahydro-1H-benzoimidazol-5-ylamine dihydrochloride salt (42g, 200 mmol) (Preparation 8) into 350 ml H₂O. Add to this solutionsodium bicarbonate (50 g, 600 mmol) portion wise until bubbling ceases.Heating to 60° C. may be needed for complete quenching of the salt. Thefinal pH is 10. Concentrate this aqueous mixture and dry on a vacuumpump overnight. Add warm ethanol (400 ml) and stir to break up the saltsolids and filter. Repeat the extraction again. Mechanical stirring orstirring overnight may be needed to break up all the solidssufficiently. Concentrate the ethanol extractions to 800 ml and add 400ml H₂O and dibenzyl-D-tartaric acid (75 g, 210 mmol). Solids form within10-15 min. Allow this mixture to stir overnight. Filter solids to give4,5,6,7-Tetrahydro-3H-benzoimidazol-5-ylamine dibenzoyl-D-tartrate whichis re-crystallized by dissolving the material in methanol (350 mL) byheating at 50-60° C. in a conical flask by continuous stirring. Addadditional methanol as need to dissolve all material. Add water (20 mL)while the mixture is hot. Cool the mixture down to room temp withstirring which results in separation of white solid suspension. Filterthe solid and dry to give enriched amino cyclohexylimidazoledibenzyl-D-tartaric acid salt. Repeat the re-crystallization procedurean additional three times to give an enriched material. Yield=25.4 g, ee˜92%.

Preparation 243-[R]-(4-benzyloxy-2,6-dichloro-benzyl)-1-(4,5,6,7-tetrahydro-3H-benzimidazole-3-yl)-pyrrolidin-2-one

Add Preparation 17 (4.87 g) to a suspension of4,5,6,7-Tetrahydro-3H-benzoimidazol-5-ylamine dibenzoyl-D-tartric acid(Preparation 23) in methanol (20 mL). Stir the mixture at roomtemperature for 30 min. Add sodium cyanoborohydride (0.75 g) and stirthe mixture for 2 h. Heat the reaction mixture at 50° C. for 2 h. Dilutethe reaction mixture with DCM (200 mL) and wash the mixture withsaturated sodium bicarbonate solution (2×100 mL), and then with water(100 mL). Dry DCM layer over sodium sulfate and concentrate on therotoevaporator to give crude. Purify the crude by silica flashchromatography eluting with a gradient of 0-5% methanol in DCM to givethe title compound (3.35 gm). MS: m/z (M+1)=470.

Preparation 253-[R]-(2,6-dichloro-4-hydroxy-benzyl)-1-(4,5,6,7-tetrahydro-3H-benzimidazol-5-yl)-pyrrolidin-2-one

Take up3-[R]-(4-Benzyloxy-2,6-dichloro-benzyl)-1-(4,5,6,7-tetrahydro-3H-benzimidazole-3-yl)-pyrrolidin-2-one(3.35 g) (Preparation 24) in methanol (30 mL) and ethyl acetate (20 mL)in a pressure bottle. Add palladium hydroxide catalyst (500 mg) and stirthe reaction mixture under hydrogen atmosphere (30 psi) at 40° C. for 4h and then at room temperature over night. Filter the reaction mixtureover celite. Concentrate filtrate to give the title compound as a whitesolid (2.69 gm). MS: m/z=379 (M+1).

Preparation 26 Trifluoro-methanesulfonic acid3,5-dichloro-4-[2-oxo-1-(3-trifluoromethanesulfonyl-4,5,6,7-tetrahydro-3H-benzimidazol-5-yl)-pyrrolidin-3-[R]-ylmethyl]-phenyland trifluoro-methanesulfonic acid3,5-dichloro-4-[2-oxo-1-(1-trifluoromethanesulfonyl-4,5,6,7-tetrahydro-3H-benzimidazol-5-yl)-pyrrolidin-3-[R]-ylmethyl]-phenylesters

Take up3-[R]-(2,6-dichloro-4-hydroxy-benzyl)-1-(4,5,6,7-tetrahydro-3H-benzimidazol-5-yl)-pyrrolidin-2-one(Preparation 25) (2.5 g) in DCM (10 mL) and pyridine (10 mL). Cool thesolution to −78° C. and add trifluorosulfonic anhydride (4 mL) drop wisewith stirring. The reaction mixture is then left standing overnight.Dilute the reaction mixture with ethyl acetate (150 mL). Wash with 1 Maqueous HCl (2×100 mL), brine (100 mL). Dry the ethyl acetate layer oversodium sulfate and concentrate on a rotary evaporator. Drying theresidue under high vacuum gives the title compound mixture as a yellowfoamy solid (3.4 g).

Preparation 27 Ethyl 2-(4-bromo-2-chlorobenzyl)-4-oxobutanoate

Add sodium periodate (41 g, 190 mmol) into a solution of ethyl2-(4-bromo-2-chlorobenzyl)pent-4-enoate (21 g, 63 mmol), 2.5 wt % OsO₄(64 g, 6.3 mmol) in THF (400 mL) and water (160 mL) and stir for 2hours. Extract the reaction mixture with ethyl acetate, wash the organiclayer with sodium thiosulfate solution and brine. Dry over sodiumsulfate, filter and concentrate. Purify the residue with silica gelcolumn to afford the title compound (15.9 g, 75%) as colorless oil.

Preparation 28(4R,5S)-(cis)-3-Pent-4-enoyl-4,5-diphenyl-oxazolidin-2-one

Dissolve (4R,5S)-(+)-cis-4,5-diphenyl-2-oxazolidin-one (2.06 g, 8.62mmol) in THF (100 mL) and cool to −78° C. Add n-BuLi (5.66 mL, 9.05mmol, 1.6 M in hexane) and stir for 30 minutes. Then add pent-4-enoylchloride (1.53 g, 12.93 mmol) and continue stir the solution for onehour. Add water (100 mL) and extract the aqueous layer with ethylacetate (3×200 mL). Combine the organic layers and dry with Na₂SO₄,filter, concentrate and purify by flash column chromatography (silicagel, 20-40% of EtOAc-hexane) to give 1.42 g (51%) of the title compoundas a white solid.

Preparation 29 3-Benzyl-1-cyclohexyl-pyrrolidin-2-one

Place 1-cyclohexyl-pyrrolidin-2-one (400 mg, 2.4 mmol) in THF (30 mL)and cool to −78° C. Slowly add LDA (2.0 M, 2.4 mL, 4.8 mmol) and stirfor 15 minutes. Add benzyl bromide (1.23 g, 7.2 mmol) and stir for 3hours. Quench with ammonium chloride and extract with dichloromethane.Dry over sodium sulfate, filter, and concentrate. Purify by silica gel(20-50% ethyl acetate in hexanes) to afford 432 mg (70%) of the titlecompound. Mass spectrum (apci) m/z=258.2 (M+H).

Preparation 30(4R,5S)-(cis)-3-[2-(S)-(2-Chloro-6-fluoro-benzyl)-pent-4-enoyl]-4,5-diphenyl-oxazolidin-2-one

Using the procedure to synthesize Preparation 29, alkylation of(4R,5S)-(cis)-3-pent-4-enoyl-4,5-diphenyl-oxazolidin-2-one (1.48 g, 6.61mmol) with 2-bromomethyl-1-chloro-3-fluoro-benzene affords 1.28 g (62%)of the title compound as a white solid.

Preparation 31(4R,5S)-(cis)-3-(2-(R)-Chloro-6-fluoro-benzyl)-4-oxo-4-(2-oxo-4,5-diphenyl-oxazolidin-3-yl)-butyraldehyde

Dissolve(4R,5S)-(cis)-3-[2-(S)-(2-chloro-6-fluoro-benzyl)-pent-4-enoyl]-4,5-diphenyl-oxazolidin-2-one(1.28 g, 2.75 mmol) in dichloromethane (100 mL) and cool to 0° C. Bubbleozone into the solution with stirring until the solution becomes blue.Continue to stir the solution for one hour, then bubble nitrogen throughthe mixture until the blue color disappears. Add Me₂S (0.85 g, 13.75mmol) and stir the solution for 6 hours. Remove the solvent underreduced pressure and purify the residue with column chromatography(silica gel, 20-40% of EtOAc-Hexane) to give 0.45 g (35%) of the titlecompound as a colorless oil.

Preparation 323-(R)-(2-Chloro-6-fluoro-benzyl)-1-cyclohexyl-pyrrolidin-2-one

Dissolve(4R,5S)-(cis)-3-(2-(R)-chloro-6-fluoro-benzyl)-4-oxo-4-(2-oxo-4,5-diphenyl-oxazolidin-3-yl)-butyraldehyde(0.45 g, 0.97 mmol) in THF (50 mL). Add cyclohexylamine (0.19 g, 1.94mmol), and acetic acid (0.12 g, 1.94 mmol) at room temperature undernitrogen. Stir the solution for one hour and then add sodiumtriacetoxyborohydride (0.82 g, 3.88 mmol). Stir the reaction mixture forover night and then add water (50 mL). Extract the aqueous layer withdichloromethane (3×100 mL). Combine the organic layers and dry withNa₂SO₄, filter, concentrate and purify by flash column chromatography(silica gel, 20-50% of EtOAc-Hexane) to give 0.26 g (88%) of the titlecompound as a colorless oil. Mass spectrum (ion spray): m/z=310.1, 312.2(M+1).

EXAMPLE 11-(4,5,6,7-Tetrahydro-3H-benzoimidazol-5-yl)-3-(3,5,4′-trichloro-biphenyl-4-ylmethyl)-pyrrolidin-2-one

Dissolve trifluoro-methanesulfonic acid3,5-dichloro-4-[2-oxo-1-(3-trifluoromethanesulfonyl-4,5,6,7-tetrahydro-3H-benzimidazol-5-yl)-pyrrolidin-3-ylmethyl]-phenyland trifluoro-methanesulfonic acid3,5-dichloro-4-[2-oxo-1-(1-trifluoromethanesulfonyl-4,5,6,7-tetrahydro-3H-benzimidazol-5-yl)-pyrrolidin-3-ylmethyl]-phenylesters (Preparation 14), 0.15 g, 0.23 mmol) in 2 ml of dioxane, and tothis solution, add 4-chlorophenylboronic acid (45 mg, 0.28 mmol) and 0.5mL of 2 M sodium carbonate. Purge the mixture with nitrogen for 1 minand add tetrakis(triphenylphosphene)palladium(0) (27 mg, 0.02 mmol). Capthe reaction and heat using microwave mediated heating for 45 min at 90°C. Apply the reaction to an SCX column and wash with Methanol (twocolumn volumes). Then, wash with two column volumes of 2 N NH₃ inMethanol to obtain semi-pure product. Purify further using HPLC ornormal phase chromatography to yield1-(4,5,6,7-Tetrahydro-3H-benzoimidazol-5-yl)-3-(3,5,4′-trichloro-biphenyl-4-ylmethyl)-pyrrolidin-2-oneas a white solid (60.0 mg, 44%).

MS: m/z (M+1)=476.

TABLE 1 Prepare the Examples in Table 1 essentially as described inExample 1 except that 4-chlorophenylboronic acid is replaced by thereagent as indicated in column 3. Purification of the compounds usingreverse phase HPLC chromatography results in trifluoroacetic acid saltsof the compounds. Data Example Structure and Chemical name Reagent m/z(M + 1) 2

Phenyl boronic acid 440 3

4-methoxy-carbonylboronic acid 498 4

Benzofuran-5-boronic acid 480 5

4-(morpholine-4-carbonyl)phenyl-boronic acid 539 6

3,5-dimethyl-isoxazole-4-boronicacid 459 7

Pyridine-3-boronicacid 441 8

3-chloro-4-(trifluoromethyl)-phenylboronic acid 542 9

2,4-dichlorophenylboronic acid 508 10

3-methylphenylboronic acid 454 11

4-methylphenylboronic acid 454 12

3-(trifluoro-methyl)phenylboronic acid 508 13

4-tert-butylphenylboronic acid 496 14

4-isopropoxy-phenylboronic acid 498 15

4-fluorophenyl-boronic acid 458 16

1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 44517

4-(trifluoro-methyl)phenylboronic acid 508

EXAMPLE 183-[3,5-Dichloro-4′-(4-methyl-piperazine-1-carbonyl)-biphenyl-4-ylmethyl]-1-(4,5,6,7-tetrahydro-1H-benzoimidazol-5-yl)-pyrrolidin-2-one

Dissolve the trifluoro-methanesulfonic acid3,5-dichloro-4-[2-oxo-1-(3-trifluoromethanesulfonyl-4,5,6,7-tetrahydro-3H-benzimidazol-5-yl)-pyrrolidin-3-ylmethyl]-phenyland trifluoro-methanesulfonic acid3,5-dichloro-4-[2-oxo-1-(1-trifluoromethanesulfonyl-4,5,6,7-tetrahydro-3H-benzimidazol-5-yl)-pyrrolidin-3-ylmethyl]-phenylesters (Preparation 14), (0.15 g, 0.23 mmol) in 2 ml of dioxane (0.15 g,0.23 mmol). To this solution, add4-(4-Methyl-piperazin-1-yl)-phenyl-methanoneboronic acid (69 mg, 0.28mmol) and 0.5 mL 2 M sodium carbonate. Purge the mixture with nitrogenfor 1 min and add tetrakis(triphenylphosphine)palladium(0) (27 mg, 0.02mmol). Cap the reaction and heat using microwave mediated heating for 45min at 90° C. Apply the reaction to an SCX column and wash with Methanol(two column volumes). Then wash with two column volumes of 2 N NH₃ inMethanol to obtain semi-pure product. Purify further using HPLC ornormal phase chromatography to yield3-[3,5-Dichloro-4′-(4-methyl-piperazine-1-carbonyl)-biphenyl-4-ylmethyl]-1-(4,5,6,7-tetrahydro-1H-benzoimidazol-5-yl)-pyrrolidin-2-one(110 mg). MS: m/z (M+1)=566.

TABLE 2 Prepare the Examples in Table 2 essentially as described inExample 18 except that4-(4-Methyl-piperazin-1-yl)-phenyl-methanoneboronic acid is replaced bythe reagent as indicated in column 3. Purification of the compoundsusing reverse phase HPLC chromatography results in trifluoroacetic acidsalts of the compounds. Data Example Structure and Chemical name Reagentm/z (M + 1) 19

4-(morpholine-4-carbonyl)phenyl-boronic acid 553 20

4-(4-ethyl-piperazine-1-carbonyl)-phenylboronic acid 580 21

4-(4-trifluoro-methyl)piperidine-1-carbonyl)phenyl-boronic acid 619

EXAMPLES 22 AND 233-[R]-[4-(4-fluorophenyl-2,6-dichloro-benzyl)-1-(4,5,6,7-tetrahydro-3H-benzimidazole-3-yl)-pyrrolidin-2-one

Heat a mixture of trifluoro-methanesulfonic acid3,5-dichloro-4-[2-oxo-1-(3-trifluoromethanesulfonyl-4,5,6,7-tetrahydro-3H-benzimidazol-5-yl)-pyrrolidin-3-ylmethyl]-phenyland trifluoro-methanesulfonic acid3,5-dichloro-4-[2-oxo-1-(1-trifluoromethanesulfonyl-4,5,6,7-tetrahydro-3H-benzimidazol-5-yl)-pyrrolidin-3-ylmethyl]-phenylesters (850 mg) (Preparation 20), 4-fluorophenylboronic acid (221 mg),tetrakis-triphenylphosphine palladium (16 mg), and saturated sodiumbicarbonate (1 mL) in 10 mL of DME at 90° C. in a vial. Filter thereaction through a SCX column (10 gm, Varion) with ethyl acetate (10mL). Elute the product with 1 M ammonia in methanol and concentrate todryness on rotary evaporator to give product as crude (400 mg). Purifythis material by chiral purification on a Chiralpak AD-H (4.6×150 mm)column eluting with 60:40:0.2 3A ethanol/heptane/DMEA (Flow=0.6 mL/min.)to give:

Example 22 (Isomer 1, MS: m/z (M+1)=458, Rt. 5.8 min, ee>99%, 187 mg).Example 23 (isomer 2, MS: m/z (M+1)=458, Rt. 9.7 min, ee>99%, 164 mg).

EXAMPLES 24 AND 25(R)-3-[3,5-Dichloro-4′-(morpholine-4-carbonyl)-biphenyl-4-ylmethyl]-1-(4,5,6,7-tetrahydro-1H-benzoimidazol-5-yl)-pyrrolidin-2-onehydrochloride salt

Examples 24 and 25 may be prepared essentially as described in theprocedure for Examples 22 and 23 except that 4-fluorophenylboronic acidis replaced by 4-(morpholine-4-carbonyl)phenylboronic acid. Chiralpurification gives:

Example 24 (Isomer 1, MS: m/z (M+1)=553, Rt. 7.3 min. Example 25 (Isomer2, MS: m/z (M+1)=553, Rt. 16.6 min. EXAMPLE 261-(4,5,6,7-Tetrahydro-3H-benzoimidazol-5-yl)-3-[R]-[2,6-dichloro-4(4-N,N-dimethylsulfonylphenyl)-phenyl-pyrrolidin-2-one

Dissolve Preparation 26 (0.15 g, 0.23 mmol) in 2 ml dioxane. To thissolution, add 4-N,N-dimethylsulfonylphenylboronic acid (45 mg, 0.28mmol) and 0.5 mL 2 M sodium carbonate. Purge the mixture with nitrogenfor 1 min and add tetrakis (triphenylphosphine) palladium (0) (27 mg,0.02 mmol). Cap the reaction and heat using microwave mediated heatingfor 45 min at 90° C. Apply the reaction to an SCX column and wash withMethanol (two column volumes). Then wash with two column volumes of 2 NNH₃ in Methanol to obtain semi-pure product. Purify further using HPLCor normal phase chromatography to yield1-(4,5,6,7-tetrahydro-3H-benzoimidazol-5-yl)-3-[R]-[2,6-dichloro-4(4-N,N-dimethylsulfonylphenyl)-phenyl-pyrrolidin-2-oneas a white solid (mg, 44%). MS: m/z=547 (M+1).

TABLE 3 Prepare the Examples in Table 3 essentially as described inExample 26 except that 4-N,N-dimethylsulfonylphenylboronic acid isreplaced by the reagent as indicated in column 3. Data Example Structureand Chemical name Reagent m/z (M + H) 27

4-(1-piperidinyl)-phenylboronic acidHCl 523 28

Cyclohexen-1-yl-boronic acid 444 29

4-morpholinophenyl-boronic acid 525 30

4-(N,N-dimethylamino)phenyl-boronic acid 483 31

2-pyrrolidin-1-yl-1-pyrimidine-5-phenylboronic acid 511 32

2-fluoro-6-morpholin-4-yl-pyridine-3-phenylboronic acid 544 33

Benzo[1,2,5]oxadiazole-5-phenylboronicacid 482 34

2-(1-benzothiophen-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 496 35

5-indolylboronic acid 479 36

2-methoxy-pyrimidine-5-boronicacid 472 37

4-(piperidine-1-sulfonyl)-phenylboronic acid 587 38

4-isopropyl-sulfamoylphenyl-boronic acid 561 39

4-(morpholin-1-sulfonyl)-phenylboronic acid 589 40

4-(methyl-sulfonyl)-phenylboronic acid 518 41

4-(azitidine-1-sulfonyl)-phenylboronic acid 563

EXAMPLE 423-[R]-[3,5-Dichloro-4′-(4-trifluoromethyl-piperidine-1-carbonyl)-biphenyl-4-ylmethyl]-1-(4,5,6,7-tetrahydro-3H-benzoimidazol-5-yl)-pyrrolidin-2-one

Dissolve Preparation 26 (0.10 g, 0.16 mmol) in 2 ml of dioxane. To thissolution, add (4-chlorocarbonylphenyl)boronic anhydride (52 mg, 0.31mmol), 4-trifluoromethylpiperidine hydrochloride (76 mg, 0.40 mmol) and0.5 mL 2 M sodium carbonate. Purge the mixture with nitrogen for 1 minand add tetrakis(triphenylphosphene) palladium (0) (23 mg, 0.02 mmol).Cap the reaction and heat using microwave mediated heating for 30 min at110° C. Apply the reaction to an SCX column and wash with Methanol (twocolumn volumes). Then wash with two column volumes of 2 N NH₃ inMethanol to obtain semi-pure product. Purify further using HPLC ornormal phase chromatography to yield3-(3,5-Dichloro-4′-morpholin-4-yl-biphenyl-4-ylmethyl)-1-(4,5,6,7-tetrahydro-1H-benzoimidazol-5-yl)-pyrrolidin-2-one(43 mg).

MS: m/z=625 (M+1).

EXAMPLE 43(R)-3-[3,5-Dichloro-4′-(4,4-difluoro-piperidine-1-carbonyl)-biphenyl-4-ylmethyl]-1-(4,5,6,7-tetrahydro-1H-benzoimidazol-5-yl)-pyrrolidin-2-one

Example 43 may be prepared essentially as described in Example 42 exceptthat 4-trifluoromethylpiperidine hydrochloride is replaced by4,4-difluoro-piperidine.

MS: m/z (M+1)=587.

EXAMPLE 443-(4-Bromo-2-chlorobenzyl)-1-(4,5,6,7-tetrahydro-3H-benzo[d]imidazol-5-yl)pyrrolidin-2-one,TFA salt

Using the procedure to synthesize Preparation 32 and using reagent ethyl2-(4-bromo-2-chlorobenzyl)-4-oxobutanoate (0.95 g, 2.85 mmol) and4,5,6,7-tetrahydro-3H-benzo[d]imidazol-5-amine (0.49 g, 2.85 mmol)yields 0.52 g (45%) of the title compound as a white solid. MS (APCI-posmode) m/z (rel intensity) 408.1 (80), 410.1 (100).

In the following section enzyme and functional assays are describedwhich are useful for evaluating the compounds of the invention.

11β-HSD Type 1 Enzyme assay

Human 11β-HSD type 1 activity is measured by assaying NADPH productionby fluorescence assay. Solid compounds are dissolved in DMSO to aconcentration of 10 mM. Twenty microliters of each are then transferredto a column of a 96-well polypropylene Nunc plate where they are furtherdiluted 50-fold followed by subsequent two-fold titration, ten timesacross the plate with additional DMSO using a Tecan Genesis 200automated system. Plates are then transferred to a Tecan Freedom 200system with an attached Tecan Temo 96-well head and an Ultra 384 platereader. Reagents are supplied in 96-well polypropylene Nunc plates andare dispensed individually into black 96-well Molecular Devices HighEfficiency assay plates (40 μL/well capacity) in the following fashion:9 μL/well of substrate (2.22 mM NADP, 55.5 μM Cortisol, 10 mM Tris,0.25% Prionex, 0.1% Triton×100), 3 μL/well of water to compound wells or3 μL to control and standard wells, 6 μL/well recombinant human 11β-HSDtype 1 enzyme, 2 μL/well of compound dilutions. For ultimate calculationof percent inhibition, a series of wells are added that represent assayminimum and maximum: one set containing substrate with 667 μMcarbenoxolone (background), and another set containing substrate andenzyme without compound (maximum signal). Final DMSO concentration is0.5% for all compounds, controls and standards. Plates are then placedon a shaker by the robotic arm of the Tecan for 15 seconds before beingcovered and stacked for a three hour incubation period at roomtemperature. Upon completion of this incubation, the Tecan robotic armremoves each plate individually from the stacker and places them inposition for addition of 5 μL/well of a 250 μM carbenoxolone solution tostop the enzymatic reaction. Plates are then shaken once more for 15seconds then placed into an Ultra 384 microplate reader (355EX/460EM)for detection of NADPH fluorescence.

Data for example compounds in the 11-βHSD1 assay are shown below:

Human 11- βHSD1 IC₅₀ Example Structure (nM) 1

325 15

214 29

75.4 32

175 42

143

Compounds of the invention can also tested for selectivity against11-βHSD2 in an assay similar to that described for 11-βHSD1, but usingthe 11-βHSD2 enzyme. The assay using the 11-βHSD2 enzyme can be carriedout by the methods described herein and supplemented by methods known inthe art.

Human Aortic Smooth Muscle Cell Assay

Primary human aortic smooth muscle cells (AOSMC) are cultured in 5% FBSgrowth medium to a passage number of 6, then pelleted by centrifugationand resuspended at a density of 9×10⁴ cells/mL in 0.5% FBS assay mediumcontaining 12 ng/mL hTNFα to induce expression of 11β-HSD1. Cells areseeded into 96-well tissue culture assay plates at 100 μL/well (9×10³cells/well) and incubated for 48 hours at 37° C., 5% CO₂. Followinginduction, cells are incubated for 4 hours at 37° C., 5% CO₂ in assaymedium containing test compounds then treated with 10 μL/well of 10 μMcortisone solubilized in assay medium, and incubated for 16 hours at 37°C., 5% CO₂. Medium from each well is transferred to a plate forsubsequent analysis of cortisol using a competitive fluorescenceresonance time resolved immunoassay. In solution, an allophycocyanin(APC)-cortisol conjugate and free cortisol analyte compete for bindingto a mouse anti-cortisol antibody/Europium (Eu)-anti mouse IgG complex.Higher levels of free cortisol result in diminishing energy transferfrom the Europium-IgG to the APC-cortisol complex resulting in less APCfluorescence. Fluorescent intensities for Europium and APC are measuredusing a LJL Analyst AD. Europium and APC excitation is measured using360 nm excitation and 615 nm and 650 nm emission filters respectively.Time resolved parameters for Europuium were 1000 μs integration timewith a 200 μs delay. APC parameters are set at 150 μs integration timewith a 50 μs delay. Fluorescent intensities measured for APC aremodified by dividing by the Eu fluorescence (APC/Eu). This ratio is thenused to determine the unknown cortisol concentration by interpolationusing a cortisol standard curve fitted with a 4-parameter logisticequation. These concentrations are then used to determine compoundactivity by plotting concentration versus % inhibition, fitting with a4-parameter curve and reporting the IC₅₀.

All of the examples disclosed herein demonstrate activity in the humanaortic smooth muscle cell assay with IC₅₀ of less than 300 nM. Data forexample compounds in the human aortic smooth muscle cell assay are shownbelow:

IC₅₀ Example Structure (nM) 1

6.8 15

3.2 29

0.60 32

3.0 42

4.5

Acute In Vivo Cortisone Conversion Assay

In general, compounds are dosed orally into mice, the mice arechallenged with a subcutaneous injection of cortisone at a set timepointafter compound injection, and the blood of each animal is collected sometime later. Separated serum is then isolated and analyzed for levels ofcortisone and cortisol by LC-MS/MS, followed by calculation of meancortisol and percent inhibition of each dosing group. Specifically, maleC57BL/6 mice are obtained from Harlan Sprague Dawley at average weightof 25 grams. Exact weights are taken upon arrival and the micerandomized into groups of similar weights. Compounds are prepared in 1%w-w HEC, 0.25% w-w polysorbate 80, 0.05% w-w Dow Corning antifoam#1510-US at various doses based on assumed average weight of 25 grams.Compounds are dosed orally, 200 μl per animal, followed by asubcutaneous dose, 200 μl per animal, of 30 mg/kg cortisone at 1 to 24hours post compound dose. At 10 minutes post cortisone challenge, eachanimal is euthanized for 1 minute in a CO₂ chamber, followed by bloodcollection via cardiac puncture into serum separator tubes. Once fullyclotted, tubes are spun at 2500×g, 4° C. for 15 minutes, the serumtransferred to wells of 96-well plates (Corning Inc, Costar #4410,cluster tubes, 1.2 ml, polypropylene), and the plates are frozen at −20°C. until analysis by LC-MS/MS. For analysis, serum samples are thawedand the proteins are precipitated by the addition of acetonitrilecontaining d-4-cortisol internal standard. Samples are vortex mixed andcentrifuged. The supernatant is removed and dried under a stream of warmnitrogen. Extracts are reconstituted in methanol/water (1:1) andinjected onto the LC-MS/MS system. The levels of cortisone and cortisolare assayed by selective reaction monitoring mode following positiveACPI ionization on a triple quadrupole mass spectrophotometer.

Data for example compounds in the acute in vivo cortisone conversionassay are shown below:

% Inhibition after 16 hours (dose of 10 Example Structure (mg/kg)) 29

52 32

59.2 42

98.4

Pharmaceutically acceptable salts and common methodology for preparingthem are well known in the art. See, e.g., P. Stahl, et al., HANDBOOK OFPHARMACEUTICAL SALTS: PROPERTIES, SELECTION AND USE, (VCHA/Wiley-VCH,2002); S. M. Berge, et al., “Pharmaceutical Salts,” Journal ofPharmaceutical Sciences, Vol. 66, No. 1, January 1977. The compounds ofthe present invention are preferably formulated as pharmaceuticalcompositions administered by a variety of routes. Most preferably, suchcompositions are for oral administration. Such pharmaceuticalcompositions and processes for preparing same are well known in the art.See, e.g., REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY (A. Gennaro,et al., eds., 19^(th) ed., Mack Publishing Co., 1995).

The particular dosage of a compound of formula (I) or a pharmaceuticallyacceptable salt thereof required to constitute an effective amountaccording to this invention will depend upon the particularcircumstances of the conditions to be treated. Considerations such asdosage, route of administration, and frequency of dosing are bestdecided by the attending physician. Generally, accepted and effectivedose ranges for oral or parenteral administration will be from about 0.1mg/kg/day to about 10 mg/kg/day which translates into about 6 mg to 600mg, and more typically between 30 mg and 200 mg for human patients. Suchdosages will be administered to a patient in need of treatment from oneto three times each day or as often as needed to effectively treat adisease selected from those described herein.

One skilled in the art of preparing formulations can readily select theproper form and mode of administration depending upon the particularcharacteristics of the compound selected, the disorder or condition tobe treated, the stage of the disorder or condition, and other relevantcircumstances. (Remington's Pharmaceutical Sciences, 18th Edition, MackPublishing Co. (1990)). The compounds claimed herein can be administeredby a variety of routes. In effecting treatment of a patient afflictedwith or at risk of developing the disorders described herein, a compoundof formula (I) or a pharmaceutically acceptable salt thereof can beadministered in any form or mode that makes the compound bioavailable inan effective amount, including oral and parenteral routes. For example,the active compounds can be administered rectally, orally, byinhalation, or by the subcutaneous, intramuscular, intravenous,transdermal, intranasal, rectal, occular, topical, sublingual, buccal,or other routes. Oral administration may be preferred for treatment ofthe disorders described herein. In those instances where oraladministration is impossible or not preferred, the composition may bemade available in a form suitable for parenteral administration, e.g.,intravenous, intraperitoneal or intramuscular.

1. A compound structurally represented by the formula:

wherein: R¹ is —H, -halogen, —O—CH₃ (optionally substituted with one tothree halogens), or —CH₃ (optionally substituted with one to threehalogens); R² is —H, -halogen, —O—CH₃ (optionally substituted with oneto three halogens), or —CH₃ (optionally substituted with one to threehalogens); R³ is —H or -halogen; R⁴ is —OH, -halogen, cyano,—(C₁-C₄)alkyl(optionally substituted with one to three halogens),—(C₁-C₆)alkoxy (optionally substituted with one to three halogens),—SCF₃, —C(O)O(C₁-C₄)alkyl, —(C₃-C₈)cycloalkyl,—O-phenyl-C(O)O—(C₁-C₄)alkyl, —CH₂-phenyl, —NHSO₂—(C₁-C₄)alkyl,—NHSO₂-phenyl(R²¹)(R²¹), —(C₁-C₄)alkyl-C(O)N(R¹⁰)(R¹¹),

wherein the dashed line represents the point of attachment to the R⁴position; R⁵ is —H, -halogen, —(C₁-C₄)alkyl(optionally substituted with1 to 3 halogens), —C(O)OH, —C(O)O—(C₁-C₄)alkyl, —C(O)—(C₁-C₄)alkyl,—O—(C₁-C₄)alkyl(optionally substituted with 1 to 3 halogens),—SO₂—(C₁-C₄)alkyl, —N(R⁸)(R⁸),

wherein the dashed line represents the point of attachment to theposition indicated by R⁵; wherein m is 1, 2, or 3; wherein n is 0, 1, or2, and wherein when n is 0, then “(CH₂)n” is a bond; R⁶ is —H, -halogen,—CN, or —(C₁-C₄)alkyl(optionally substituted with 1 to 3 halogens); R⁷is —H, -halogen, or —(C₁-C₄)alkyl(optionally substituted with 1 to 3halogens); R⁸ is independently at each occurrence —H,—(C₁-C₆)alkyl(optionally substituted with 1 to 3 halogens),—C(O)(C₁-C₆)alkyl(optionally substituted with 1 to 3 halogens),—C(O)—(C₃-C₈)cycloalkyl, —S(O₂)—(C₃-C₈)cycloalkyl or—S(O₂)—(C₁-C₃)alkyl(optionally substituted with 1 to 3 halogens); R⁹ is—H or -halogen; R¹⁰ and R¹¹ are each independently —H or —(C₁-C₄)alkyl,or R¹⁰ and R¹¹ taken together with the nitrogen to which they areattached form piperidinyl, piperazinyl, or pyrrolidinyl; R²⁰ isindependently at each occurrence —H, or —(C₁-C₃)alkyl(optionallysubstituted with 1 to 3 halogens); R²¹ is independently at eachoccurrence —H, -halogen, or —(C₁-C₃)alkyl(optionally substituted with 1to 3 halogens); R²² is independently at each occurrence —H or—(C₁-C₆)alkyl(optionally substituted with 1 to 3 halogens); and R²³ isindependently at each occurrence —H, —(C₁-C₄)alkyl, or—C(O)O—(C₁-C₄)alkyl; or a pharmaceutically acceptable salt thereof.
 2. Acompound of claim 1 structurally represented by the formula:

wherein: R⁰ is

or a pharmaceutically acceptable salt thereof.
 3. A compound of claim 2wherein R¹ and R² are chlorine, or a pharmaceutically acceptable saltthereof.
 4. A compound of claim wherein R³ is hydrogen, or apharmaceutically acceptable salt thereof.
 5. A compound of claim 4wherein R⁰ is

or a pharmaceutically acceptable salt thereof.
 6. A compound of claim 4wherein R⁰ is

or a pharmaceutically acceptable salt thereof.
 7. A compound of claim 4wherein R⁴ is

and R⁷ is hydrogen, or a pharmaceutically acceptable salt thereof.
 8. Acompound of claim 4 wherein R⁴ is

and R⁶ is hydrogen, or a pharmaceutically acceptable salt thereof.
 9. Acompound of claim 8 wherein R⁵ is

and R⁸ is —(C₁-C₃)alkyl(optionally substituted with 1 to 3 halogens), ora pharmaceutically acceptable salt thereof.
 10. A compound of claim 8wherein R⁵ is chlorine or fluorine, or a pharmaceutically acceptablesalt thereof.
 11. A compound of claim 8 wherein R⁵ is fluorine, or apharmaceutically acceptable salt thereof.
 12. A compound that is(R)-3-(3,5-Dichloro-4′-morpholin-4-yl-biphenyl-4-ylmethyl)-1-(4,5,6,7-tetrahydro-1H-benzoimidazol-5-yl)-pyrrolidin-2-oneor a pharmaceutically acceptable salt thereof.
 13. A compound that is3-(3,5-Dichloro-4′-fluoro-biphenyl-4-ylmethyl)-1-(4,5,6,7-tetrahydro-1H-benzoimidazol-5-yl)-pyrrolidin-2-one,or a pharmaceutically acceptable salt thereof.
 14. A compound that is3-[R]-[3,5-Dichloro-4′-(4-trifluoromethyl-piperidine-1-carbonyl)-biphenyl-4-ylmethyl]-1-(4,5,6,7-tetrahydro-3H-benzoimidazol-5-yl)-pyrrolidin-2-one,or a pharmaceutically acceptable salt thereof.
 15. A pharmaceuticalcomposition which comprises a compound of claim 1, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier. 16.(canceled)
 17. A method for treating metabolic syndrome in a patient inneed thereof which comprises administering to said patient an effectiveamount of a compound of claim 1, or a pharmaceutically acceptable saltthereof.
 18. A method for treating type 2 diabetes in a patient in needthereof which comprises administering to said patient an effectiveamount of a compound of claim 1, or a pharmaceutically acceptable saltthereof.
 19. A method for treating atherosclerosis in a patient in needthereof which comprises administering to said patient an effectiveamount of a compound of claim 1, or a pharmaceutically acceptable saltthereof.
 20. A compound that-is


21. A compound of claim 1 selected from the group consisting of:1-(4,5,6,7-Tetrahydro-3H-benzoimidazol-5-yl)-3-(3,5,4′-trichloro-biphenyl-4-ylmethyl)-pyrrolidin-2-one;3-(3,5-Dichloro-biphenyl-4-ylmethyl)-1-(4,5,6,7-tetrahydro-1H-benzoimidazol-5-yl)-pyrrolidin-2-one;3′,5′-Dichloro-4′-[2-oxo-1-(4,5,6,7-tetrahydro-1H-benzoimidazol-5-yl)-pyrrolidin-3-ylmethyl]-biphenyl-4-carboxylicacid methyl ester;3-(4-Benzofuran-5-yl-2,6-dichloro-benzyl)-1-(4,5,6,7-tetrahydro-1H-benzoimidazol-5-yl)-pyrrolidin-2-one;3-(3,5-Dichloro-4′-morpholin-4-ylmethyl-biphenyl-4-ylmethyl)-1-(4,5,6,7-tetrahydro-1H-benzoimidazol-5-yl)-pyrrolidin-2-one;3-[2,6-Dichloro-4-(3,5-dimethyl-isoxazol-4-yl)-benzyl]-1-(4,5,6,7-tetrahydro-1H-benzoimidazol-5-yl)-pyrrolidin-2-one;3-(2,6-Dichloro-4-pyridin-3-yl-benzyl)-1-(4,5,6,7-tetrahydro-1H-benzoimidazol-5-yl)-pyrrolidin-2-one;1-(4,5,6,7-Tetrahydro-1H-benzoimidazol-5-yl)-3-(3,5,3′-trichloro-4′-trifluoromethyl-biphenyl-4-ylmethyl)-pyrrolidin-2-one;3-(3,5,2′,4′-Tetrachloro-biphenyl-4-ylmethyl)-1-(4,5,6,7-tetrahydro-1H-benzoimidazol-5-yl)-pyrrolidin-2-one;3-(3,5-Dichloro-3′-methyl-biphenyl-4-ylmethyl)-1-(4,5,6,7-tetrahydro-1H-benzoimidazol-5-yl)-pyrrolidin-2-one;3-(3,5-Dichloro-4′-methyl-biphenyl-4-ylmethyl)-1-(4,5,6,7-tetrahydro-1H-benzoimidazol-5-yl)-pyrrolidin-2-one;3-(3,5-Dichloro-3′-trifluoromethyl-biphenyl-4-ylmethyl)-1-(4,5,6,7-tetrahydro-1H-benzoimidazol-5-yl)-pyrrolidin-2-one;3-(4′-tert-Butyl-3,5-dichloro-biphenyl-4-ylmethyl)-1-(4,5,6,7-tetrahydro-1H-benzoimidazol-5-yl)-pyrrolidin-2-one;3-(3,5-Dichloro-4′-isopropoxy-biphenyl-4-ylmethyl)-1-(4,5,6,7-tetrahydro-1H-benzoimidazol-5-yl)-pyrrolidin-2-one;3-(3,5-Dichloro-4′-fluoro-biphenyl-4-ylmethyl)-1-(4,5,6,7-tetrahydro-1H-benzoimidazol-5-yl)-pyrrolidin-2-one;3-[2,6-Dichloro-4-(1-methyl-1H-pyrazol-4-yl)-benzyl]-1-(4,5,6,7-tetrahydro-1H-benzoimidazol-5-yl)-pyrrolidin-2-one;3-(3,5-Dichloro-4′-trifluoromethyl-biphenyl-4-ylmethyl)-1-(4,5,6,7-tetrahydro-1H-benzoimidazol-5-yl)-pyrrolidin-2-one;3-[3,5-Dichloro-4′-(4-methyl-piperazine-1-carbonyl)-biphenyl-4-ylmethyl]-1-(4,5,6,7-tetrahydro-1H-benzoimidazol-5-yl)-pyrrolidin-2-one;3-[3,5-Dichloro-4′-(morpholine-4-carbonyl)-biphenyl-4-ylmethyl]-1-(4,5,6,7-tetrahydro-1H-benzoimidazol-5-yl)-pyrrolidin-2-one;3-[3,5-Dichloro-4′-(4-ethyl-piperazine-1-carbonyl)-biphenyl-4-ylmethyl]-1-(4,5,6,7-tetrahydro-1H-benzoimidazol-5-yl)-pyrrolidin-2-one;3-[3,5-Dichloro-4′-(4-trifluoromethyl-piperidine-1-carbonyl)-biphenyl-4-ylmethyl]-1-(4,5,6,7-tetrahydro-1H-benzoimidazol-5-yl)-pyrrolidin-2-one;3-[R]-[4-(4-fluorophenyl-2,6-dichloro-benzyl)-1-(4,5,6,7-tetrahydro-3H-benzimidazole-3-yl)-pyrrolidin-2-one;(R)-3-[3,5-Dichloro-4′-(morpholine-4-carbonyl)-biphenyl-4-ylmethyl]-1-(4,5,6,7-tetrahydro-1H-benzoimidazol-5-yl)-pyrrolidin-2-one;1-(4,5,6,7-Tetrahydro-3H-benzoimidazol-5-yl)-3-[R]-[2,6-dichloro-4(4-N,N-dimethylsulfonylphenyl)-phenyl-pyrrolidin-2-one;(R)-3-(3,5-Dichloro-4′-piperidin-1-yl-biphenyl-4-ylmethyl)-1-(4,5,6,7-tetrahydro-1H-benzoimidazol-5-yl)-pyrrolidin-2-one;(R)-3-(2,6-Dichloro-4-cyclohex-1-enyl-benzyl)-1-(4,5,6,7-tetrahydro-1H-benzoimidazol-5-yl)-pyrrolidin-2-one;(R)-3-(3,5-Dichloro-4′-morpholin-4-yl-biphenyl-4-ylmethyl)-1-(4,5,6,7-tetrahydro-1H-benzoimidazol-5-yl)-pyrrolidin-2-one;(R)-3-(3,5-Dichloro-4′-dimethylamino-biphenyl-4-ylmethyl)-1-(4,5,6,7-tetrahydro-1H-benzoimidazol-5-yl)-pyrrolidin-2-one;(R)-3-[2,6-Dichloro-4-(2-pyrrolidin-1-yl-pyrimidin-5-yl)-benzyl]-1-(4,5,6,7-tetrahydro-1H-benzoimidazol-5-yl)-pyrrolidin-2-one;(R)-3-[2,6-Dichloro-4-(2-fluoro-6-morpholin-4-yl-pyridin-3-yl)-benzyl]-1-(4,5,6,7-tetrahydro-1H-benzoimidazol-5-yl)-pyrrolidin-2-one;(R)-3-(4-Benzo[1,2,5]oxadiazol-5-yl-2,6-dichloro-benzyl)-1-(4,5,6,7-tetrahydro-1H-benzoimidazol-5-yl)-pyrrolidin-2-one;(R)-3-(4-Benzo[b]thiophen-5-yl-2,6-dichloro-benzyl)-1-(4,5,6,7-tetrahydro-1H-benzoimidazol-5-yl)-pyrrolidin-2-one;(R)-3-[2,6-Dichloro-4-(1H-indol-5-yl)-benzyl]-1-(4,5,6,7-tetrahydro-1H-benzoimidazol-5-yl)-pyrrolidin-2-one;(R)-3-[2,6-Dichloro-4-(2-methoxy-pyrimidin-5-yl)-benzyl]-1-(4,5,6,7-tetrahydro-1H-benzoimidazol-5-yl)-pyrrolidin-2-one;(R)-3-[3,5-Dichloro-4′-(piperidine-1-sulfonyl)-biphenyl-4-ylmethyl]-1-(4,5,6,7-tetrahydro-1H-benzoimidazol-5-yl)-pyrrolidin-2-one;3′,5′-Dichloro-4′-[(R)-2-oxo-1-(4,5,6,7-tetrahydro-1H-benzoimidazol-5-yl)-pyrrolidin-3-ylmethyl]-biphenyl-4-sulfonicacid isopropylamide;(R)-3-[3,5-Dichloro-4′-(morpholine-4-sulfonyl)-biphenyl-4-ylmethyl]-1-(4,5,6,7-tetrahydro-1H-benzoimidazol-5-yl)-pyrrolidin-2-one;(R)-3-[3,5-Dichloro-4′-(methylsulfonyl)-biphenyl-4-ylmethyl]-1-(4,5,6,7-tetrahydro-1H-benzoimidazol-5-yl)-pyrrolidin-2-one;(R)-3-[3,5-Dichloro-4′-(azitidine-4-sulfonyl)-biphenyl-4-ylmethyl]-1-(4,5,6,7-tetrahydro-1H-benzoimidazol-5-yl)-pyrrolidin-2-one;3-[R]-[3,5-Dichloro-4′-(4-trifluoromethyl-piperidine-1-carbonyl)-biphenyl-4-ylmethyl]-1-(4,5,6,7-tetrahydro-3H-benzoimidazol-5-yl)-pyrrolidin-2-one;(R)-3-[3,5-Dichloro-4′-(4,4-difluoro-piperidine-1-carbonyl)-biphenyl-4-ylmethyl]-1-(4,5,6,7-tetrahydro-1H-benzoimidazol-5-yl)-pyrrolidin-2-one;and3-(4-Bromo-2-chlorobenzyl)-1-(4,5,6,7-tetrahydro-3H-benzo[d]imidazol-5-yl)pyrrolidin-2-one;or a pharmaceutically acceptable salt thereof.